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SUMMARY OF OPENING STATEMENT 

Director, National Institutes of Heaitn 
Public Health Service 

i960 ESTIMATE 



Mr. Jhairman and Members of the Committee: 

The statement concerns the 196O programs of medical research, 
research training, and related activities of the National Institutes of 
Health, Public Health Service. 

Stability of support is highly important to medical research. 
Grantee institutions, largely dependent on outside support for their 
research activity, have confidence in the stability of funds provided 
through NIH appropriations and endorse the policies under which the funds 
are made available. 

In summarizing 1959 operations, the statement reviews the stated 
wishes and expectations of Congress- -that sound research should not be 
limited by lack of funds, that resources for future research should expand 
as a result of training and construction programs, that certain program 
areas should receive special attention, that basic studies should be 
strongly supported, and that funds should not be shifted among programs 
if the designated use is not immediately feasible. 

Major program developments of recent months are enumerated: 
(1) NIH continued, with the aid of non-Federal groups, to appraise its 
own programs; (2) through increased funds, research was augmented in 
medical schools and other grantee institutions; (3) a position of NIH 



Associate Director for Training was established to meet growing respon- 
sibilities in fellowship and training grant areas; {h) relations with 
the pharmaceutical and chemical industry were clarified; (5) a Division 
of General Medical Sciences was created, with "broad research grant and 
training functions; (6) progress was made in large-scale collaborative 
programs- -cancer chemotherapy, psychopharmacology, perinatal studies; 
(7) productive research was stimulated in such special areas as gastro- 
enterology and cystic fibrosis; (8) initial steps were taken in long- 
range efforts to develop the field of physical biology and to investigate 
cancer- causing viruses; (9) there \i3.s mounting evidence that an expansion 
of international NIH activities would be fruitful; (lO) the NIH staff at 
Bethesda made notable advances, continuing to work effectively with the 
entire scientific community; (ll) four major building projects at Bethesda 
progressed satisfactorily; and (12) after five years of occupany and 12,000 
patient admissions, the Clinical Center gave evidence that it is fulfilling 
its promise as a research facility. 

For i960, appropriations are requested to continue operations at 
the level of the 1959 appropriations, except for a reduction from $30 million 
to $20 million for research construction grants. Individual program 
directors will discuss their I960 program plans. 

Looking toward the future, NIH is conducting an intensive study of 
research needs and NIH support in 20 selected medical schools. Preliminary 
results and other data reveal trends toward increasingly productive medical 



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research through attention to the broader needs of institutions, stronger 
training programs, collaborative studies, freedom of inquiry, better 
communications, and balanced research support. Substantive trends may 
bring extensions of physical biology, behavioral sciences, epidemiology, 
environmental health studies, and probings into the secrets of the cell. 



OPENING STATEMENT 

Director, National Institutes of Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 



Mr. Chairman and Members of the Cozmnittee: 

It is again my privilege to appear before you on behalf of the 
Public Health Service's medical reseaurch, research training, and related 
activities which comprised the National Institutes of Health. 

In making the appropriation requests for our programs in I96O, 
I must first express to the Committee, both for n^rself and my colleagues, 
and on behalf of the scientists and institutions directly affected and 
the millions of people directly and indirectly benefited, the deep 
appreciation we all feel for the fair and thorough consideration given 
to our appropriation requests each yekr. You have had the interest and 
taken the time to study what we do in detail; you have had the wisdom, 
recognizing that medical research is a truly national endeavor, to give 
audience to a diverse group of non-Federal leaxiers in science and public 
affairs before reaching a decision on these appropriations; and you have 
had the vision and judgment to create and maintain stability as an es- 
sential aspect of these programs. 

The Institute directors and I welcome your inquiry into our 
activities at the National Institutes of Health and will do everything 
we can to provide the information you want and need in order to carry 
out the Committee's business. 



- 2 - 

Stability as a factor in the support of medical research 

Before reporting to you on the use of funds provided by the 
Congress for NIH programs in 1959^ I would like, if I may, to say a 
further word about stability. 

One might think there is something antithetical in annual ap- 
propriations for a stable research effort. Certainly the possibility 
of fluctuation in level of support is inherent in Federal as it is in 
all financing on a yearly basis. In research, a sense of fiscal in- 
security could do irreparable damage. A scientist wants to feel he can 
complete a study upon which he embarks. The leader of a research team 
won't gather together a group of co-workers for a long-term project 
without being s\ire of the commitments he can make to them. A professor 
who is willing to head a new training program to develop additional 
scientific manpower in a shortage area must not fear withdrawal of 
support before his program has had time to produce results. Institu- 
tions which receive sizable funds from outside sources for research 
and training projects can plan and program adequately only if there is 
continuity in such support. 

The factor of stability has been demonstrated to obtain in the 
programs whose appropriation requests are now before you. We are 
never challenged by grantees or grantee institutions with the question 
of whether or not the Congress will provide funds to meet our moral 
commilaiients . This is something of which the Congress may justly be 



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proud. I stress it here because as the National Institutes of Health 
programs have grown and broadened, they have become a vital component of 
the national effort, in terms of both current support and research potential. 
They provide nearly ^0 percent of the funds that are available from all 
so\irces for resesirch in the health sciences. Those individuals and 
institutions who are the recipients of these funds have confidence in 
their source. They strongly endorse the policies under which the funds 
are made available — policies to which members of this Committee have 
contributed significantly. And they respond by developing creative re- 
search environments from which emerge findings that are intimately related 
to the better health of the American people. 
General progress in National Institutes of Health programs 

In discussing the National Institutes of Health I96O appropriation 
requests with a committee of Congress, one finds it difficult to know where 
to break into a continuum that began before 1900^ was sustained through 
several decades of distinguished contribution in the nutritional and 
commimicable diseases, and developed in its present-day sense from about 
19^5* There are several who will take part in these hearings, including 
the Chairman of this committee, who have first-hand knowledge of each 
step since then in the forward march of these programs. It would be 
enlightening to any new members of the Committee and a pleasure for me 
were I to describe the steps: the initiation of the resesurch grants 
program; the development of each of the Institutes; the start of fellowships 



- k - 

at predoctoral and postdoctoral levels; the planning, construction, and 
occupancy of the Clinical Center; the progressive importance of training 
grants and awards; the addition of authorization to give grants to assist 
in the construction of research facilities; the use of program grants in 
certain areas, and the gradual increase in the size and duration of other 
research project grants; the strengthening of all programs, both research 
and training; in the fundamental sciences. There is almost no end to the 
steps that covild be recalled during our growth and maturation process. 
All that can be done here is to reassure the Committee that it has been 
a satisfying and productive period of growth and change. This is confirmed 
by the nature and dimension of the research activity in Bethesda and in the 
more than TOO non-Federal institutions which are recipients of grant 
and award support derived from appropriations provided by the Congress 
for them, and through us. 
Considerations governing FY 1959 operations 

My report to you on what has been accomplished through National 
Institutes of Health appropriations in 1959 should begin with a recapitu- 
lation of the essential fiscal and functional situation presented by your 
actions. 

The 1958 appropriation level, exclusive of construction, was 
$211.1 million. This was increased to a program authorization of $29^-3 
million in 1959^ or an increase of $83.2 million. 



- 5 - 
A study of the hearings and reports of Congress^ as related to 
these appropriations, reveals six primaiy observations and instructions 
of Congress to be applied in the expenditure of these funds, as follows: 

(1) The Congress wished to assure that fund limitations in them- 
selves should not be a barrier to the performance of medical research 
judged to be worthy of support, provided this can be accomplished in 
facilities that are suitable and by scientists of competence. 

(2) The Congress anticipated fvirther expansion of medical research 
in the future, supported by diverse sovirces, as evidenced by the striking 
increase in the funds devoted to the training of future research investi- 
gators . 

(3) The Congress accepted the advice of various counselors that 
certain program areas require special attention, in that they are ready 
either for developmental research or for a broadening of the base of funda- 
mental studies already under way. 

(k) Although there was extensive earmarking of funds for specific 
research targets, the Congress again emphasized the need for the conduct 
of research and training in the sciences basic to medicine. 

(5) The Congress continued to express high confidence in the 
National Institutes of Health direct operations. 

(6) The Congress expected the National Institutes of Health to 
program effectively as much of the total appropriation as feasible; however, 
in its injunctions not to sacrifice quality standards in undertaking the 



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expansion, the Congress gave implicit recognition to the fact that facilities, 
or personnel shortages, or particularly time limitations might make the 
fvill expansion impossible within the fiscal year. In this connection, the 
Congress enjoined us against the transfer of funds out of the program 
area for which they were appropriated in order to meet deficits in some 
other area. 

We have carried out your wishes to the very best of our ability. 
In particiilar, we have given attention to the maintenance of the quality 
standards which have become conventional. We have also made a major effort 
to engender interest and substantial program levels in areas identified 
as having special promise. 
A summation of 19^9 operations 

The product of our effort can be subjected to many kinds of 
assessment. In fiscal terms, our initial projections developed last summer 
indicated an ability to program $7^*2 million of our 1959 increases, 
leaving $9 million in unprogrammed sums. The bulk of the unprogrammed 
funds were in research grants and in fellowships and training grants and 
awards. This prediction was the result of three factors: our unwillingness, 
and that of owe advisors, to compromise on questions of quality; our 
inability to use excess fxonds in one budget activity to meet needs in 
another; and the inherent difficulty in mounting sizable programs in new 
research areas in the span of a few months. 



- 7 - 

As the fiscal year has evolved, it now appears that certain of our 
projections need to he modified. A number of our programs have developed 
more rapidly than was indicated in our original predictions; some have 
developed more slowly. Upon completion of definitive analyses, currently 
in progress, proposals to modify our current apportionments will be made. 

The product of our efforts in the past year in program terms is 
gratifying indeed. And the product of our investigators and the scientists 
receiving grants, in terms of research findings directly and ultimately 
related to the control of disease in man, once again confirms the funda- 
mental premise that in research lies the promise of dramatic reduction 
of the biological and behavioral impairments which cause extended 
disability or premature death — a promise which, for many conditions, has 
already become a reality. 

I shall not undertake to summarize either the program developments 
or the research highlights of the past year resulting from the individual 
National Institutes of Health appropriations. Such testimony can be 
better and more appropriately presented by the Institute Directors, who 
are looking forward to discussing with you the major developments in 
their fields of special interest. In addition, we shall be happy to 
make available to you some prepared materials which indicate the 
accomplishments in each field of study. 



- 8 - 

Rather, as Director of the National Institutes of Health, I should 
like to bring to the Committee ' s attention some of the major general 
developments in FY 1959 affecting the National Institutes of Health as 
a vhole. I ask your indulgence to do this in the form of simple enumeration. 
Vfy colleagues and I are prepared to elaborate on any item that has special 
interest for the Committee. 
Program developments-1959 

These are some of the important program elements that have emerged 
in recent months. 

(1) We have engaged in an intensive and multi -faceted appraisal 

of the impact of the effectiveness of our present programs and their impact 
on the individuals and institutions making up the community of medical 
science. With the assistance and cooperation of outside groups, these 
studies --which are only a step in what I am convinced must be a continual 
process of analysis and self -appraisal — will provide essential information 
to guide us in the evolution of our programs in the years ahead. 

(2) With an increase of $44.2 million over FY 1958 for research 
project grants, it has been possible to strengthen both the substance of 
medical research in the medical schools, universities, and related 
institutions, and at the same time to strengthen the research component 
of the institutions themselves. New study sections have been added to 
permit the review of applications that were more numerous and representative 
of more diverse research fields without compromising the quality of review. 



- 9 - 
The pressing problem in the research grants program continues to be the 
inability to compensate the already hard-pressed schools for the full 
amount of the indirect costs of conducting research supported by Public 
Health Service grants. 

(3) The National Institutes of Health training and fellowships 
programs which have grown from $17 million in FY 195^ to $60 million in 
FY 1959^ in recognition of the overriding importance of scientific manpower 
to the research effort in the years ahead, have given every evidence of 
effectiveness in meeting this need. In recognition of the consequence 
of this program area, the Surgeon General accepted my recommendation (at 
the same time as Dr. Van Slyke received long-overdue recognition by being 
appointed to the newly created post of Deputy Director of the National 
Institutes of Health) to establish a National Institutes of Health 
Associate Director for Training and to elevate to this position Dr. Kenneth 
M. Endicott, who had directed our cancer chemotherapy program so brilliantly. 

(k) During the year, through a series of meetings, publications, 
and other steps reflecting in large measure the spontaneous interest of 
industry, better understandings were achieved with leaders of the 
pharmaceutical and chemical industry with respect to their participation 
in the national medical research effort. Mong the questions vinder 
discussion were the support of certain resesurch in industry by the 
National Institutes of Health contracts and grants, patent and other problems 
involved when industry research is supported by tax funds, and the respec- 
tive interests of industry and government in the whole field of drxig 
research and devdopment. 



- 10 - 

(5) A major organizational development has been the creation of 
a Division of General Medical Sciences. Formed from research grant and 
training activities of the Division of Research Grants, and also incor- 
porating the Center for Research on Aging, this program change has been 
made in recognition of two primary factors: first, the size and impor- 
tance of the program itself, directed largely to the pre-clinical sciences 
and those areas of f\mdamental inquiry unrelated to the mission of any 
Institute; and second, the increasing stress that must be placed on both 
the scientific review processes of our grants programs and their continued 
evaluation and analysis, making it essential for the Division of Research 
Grants to be divorced from the bulk of its direct operating programs so 

it can concentrate on these National Institutes of Health wide services 
to all of the extramural activities. 

(6) Satisfying progress has been made in the several large-scale, 
long-term collaborative programs — the search for better chemical agents 
to treat cancer, the evaluation of the mode of action and therapeutic 
efficacy of psychopharmacologic agents, the effort to uncover the pre- 
natal and postnatal influences that may be related to the causation of 
such conditions as mental retardation and cerebral palsy. These repre- 
sent major segments of our investment in research, and we are doing 
everything we can to see that they evolve in an orderly and efficient 
fashion which will yield not only answers in their target areas but also 
basic knowledge which may be applicable to the understanding and solution 
of other medical and public health problems. 



- 11 - 

(7) In other special research areas of demonstrated interest to 
the Committee — areas such as gastroenterology, staphylococcus infection, 
cystic fibrosis, schizophrenia, new drugs in heart disease — the forward 
movements has been gratifying but less uniform. The Committee is well 
aware, as we are, that when essentially new and additive areas of research 
interest are superimposed on medical science, as a result of the awareness 
of deficits in those areas and the stimulus provided by the availability 
of f\mds earmarked for this pvirpose, it is not always possible to combine 
research interest and available facilities to produce an effective program 
in any given yesir. When such special effort is made to develop a new 
field over a period of several years, however, it is evident from our 
experience that the interest, competence, and facilities can be mobilized 
and the potential for progress in the specified field thereby enhanced. 

(8) Among the developments of the past year of a general nature 
which augur well for the future are those related to the initial, formu- 
lative steps towajrd applying the knowledge, skills, and instrumentation 
of the physical sciences to biological problems, and mounting a broadly 
based exploration of the many interesting leads related to the possible 
viral origin of cancer. It is when one undertakes to help set such programs 
in motion, programs that cannot accurately be evaluated until 5-10 years 
have passed, that he particxilarly appreciates the understanding this 
Committee exhibits concerning science and its processes. When it is 



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possible to view FY 1959 in perspective, it may be that the investments 
made in such fields will have been the most significant aspect 
of our programs. 

(9) In our own facilities at Bethesda and in the field, there 
has been steady progress resulting in part from the quality of the 
individual scientists and the special opportionity afforded them by 
our facilities, and in part from a developing sense of cohesiveness 
and purpose. The latter aspect is in no small measure related to the 
leadership and stimulus provided by our tnily outstanding group of 
scientific directors and the National Institutes of Health Associate 
Director with whom they are closely associated in program planning, 
Dr. Joseph E. Smadel. Our staff and our facilities continue to work 
effectively with the entire community of medical science, and ex- 
cellence continues to be the governing factor now that the period 

of growth has been largely accomplished. 

(10) In terms of the new construction at Bethesda that has 
been authorized and/or financed by the Congress, there are four major 
projects to be reported on: 

a. The new building to house the Division of Biologies 
Standards is well along, on or perhaps even ahead of schedule. The 
builders expect it to be ready for occupancy before the end of 1959> 



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and our scientific staff is Looking forward to re -occupancy of the 
space they^ in our common interest, had to give up to permit temporary 
housing of the expanded work, both regxilatory and research, of this 
program so vitally concerned with the development and control of 
biological products. 

b. Contracts are about to be let for the basic structure 
which will extend the surgical facilities of the Clinical Center. We 
have spent a great deal of time in the design and planning of this 
vinique surgical wing, tailored to the specialized needs of research 
in neuros\irgery and cardiovascular surgery. The resulting facility, 
scheduled for completion in 19^0, will be a model of its kind and 
represent the most modem concepts of the utilization of space and 
structure to serve a program in research surgery. 

c. The construction bids for the new building to house 
the laboratories of the National Institute of Dental Research have 
been received. Completion and occupancy are estimated for the fall 
of i960. 

d. The new office building is progressing with only minor 
departures from our initial estimated schedule, and plans are scheduled 



- Ik - 

to be completed on April 1, 1959 • Since the National Institutes of 
Health was planned for laboratory and clinical investigations, and was 
not planned for the essentieG-ly office functions associated with the 
grants and other support functions, the office space factor is critical. 
We are urging all possible speed on this project to permit the return to 
Bethesda of many of our staff now in rental space, mostly in Silver 
Spring, and to permit the re-conversion to laboratories and animal 
production facilities of space at Bethesda which now must be used for 
offices. 

(11) Finally, with respect to FY 1959^ I am pleased to report 
that five years of occupancy of the Clinical Center have amply demon- 
strated the capacity of that splendid structure to subserve the program 
needs of the Institutes for clinical as well as laboratory investigations. 
More than 12,000 patients have been admitted to the Clinical Center 
according to the research needs of the clinical investigators. The 
many services associated with patient care are working smoothly, the 
professional relationships with this medical community are sound, and 
the bed occupancy levels are both high enough and steady enough to 
permit the generalization that the facility is being effectively 
utilized. 



- 15 - 

The foregoing summation of our experience in FY 1959 is one that 
can be presented with pride and with confidence that the job done has been 
responsive to the wishes of Congress. 
FY i960 budget request 

The budget proposals that are before you for FY 19^0 request 
continuation of our programs in that year at the level of the appropriations 
for FY 1959^ except for a reduction from $30 million (the full amoxmt 
authorized) to $20 million in matching grants to assist in the construc- 
tion of health research facilities. Other than this, there are a few 
minor variations in the proposed allocation of funds ^ but these do not 
affect the total of any one of the Institutes or of the National Institutes 
of Health as a whole. 

The individual Institute Directors will appear before you to 
discuss what is proposed for their programs in FY 196O, and Dr. Van Slyke 
will testify on the health research facilities program. In addition this 
year, in the light of the increasing size and importance of the program 
encompassed within the Division of General Medical Science , we have asked 
the head of that program, Dr. G. Halsey Hunt, to appear before you. The 
other component of the appropriation item identified as "General Research 
and Services, National Institutes of Health" is the Division of Biologies 
Standards, whose operating performance in FY 1959 and proposals for FY 
i960 are suimnarized in an attachment to this statement. 



- 16 - 

There are also available to the Committee, should you wish them, 
statements summarizing the activities of each of the four divisions which 
provide centrally the services required to maintain the programs of the 
several Institutes — the Clinical Center, the Division of Research Grants, 
the Division of Research Services, and the Division of Business Operations. 

Just as it is difficult, in a continuum such as medical research, 
to look hack at the year just past and pick out its most important aspects, 
so it is well-nigh impossible to predict with any degree of accuracy the 
results of the year ahead in terms of discrete scientific obseirvations 
which can be applied in medical and public health practice. 

On the other hand, when one looks at the decade ahead, the patterns 
of progress begin to emerge more clearly. It is possible to perceive 
trends in the organization of medical research and in the mobilization 
of resources for its effective prosecution. And it is possible to see 
certain trends in the substance of the life sciences, and events single 
out the areas in which the major advances are most likely to occur. 
General considerations in the future of medical research 

For a wide variety of reasons and by a large number of groups, the 
future health of the Nation is under continuous, intensive study. Some 
are concerned with meeting the health challenge inherent in the rapid 
growth and changing age composition of our population. Some are concerned 
with the economics of medical care and the economic burden of disability and 
premature death. Some are concerned with our comparative, competitive 



- 17 - 
position in health relative to our sister nations of the world. Some are 
concerned with the qualitative and quantitative aspects of health programs, 
and some are directed to the question of balance between public and private 
support . 

All such studies require consideration of medical research, since 
the developaent of new knowledge is not only intimately related to, but 
often governs the characteristics of other activities which apply knowledge 
to hxaman health. 

As the Committee knows, we are in the process of studying the 
research needs of and the impact of the National Institutes of Health 
support programs on twenty selected medical schools. This study, too, is 
yielding valuable information on the shape and dimension of medical research 
in the years ahead. Yet, in the final analysis, adding up the available 
information from all sources and projecting future trends is more a sub- 
jective than it is an objective undertaking. 

In my judgment, these are some of the most important things to be 
looked for as medical research evolves in the years ahead. 

(1) There will be increasing need for those who formulate and 
carry out national policy to be concerned not just with the strength of 
the medical research effort, but with the total strength of the institutions 
of higher learning in which the bulk of such research is carried out and 
where the spirit of free inquiry flourishes. 



- 18 - 

(2) As an increasing proportion of xiniversity-oriented medical 
research is supported from outside sources, each with its own special 
mission, there will be greater urgency for the so\irces of support to 
recognize the needs of grantee institutions for making their own determina- 
tions as to the direction of their research effort and the relative 
emphasis given both to different fields of inquiry and to the balance 
between research and their other fimctions. 

(3) Since the availability of trained scientific manpower is the 
key to many of the research doors that remain locked, and since this 
factor is more likely to impede scientific progress than the availability 
of research facilities or funds for support of specific projects, there 
will be modifications and extensions of existing programs so that more 
scientists, both M.D. 's and Ph.D. 's, will be developed, and so that the 
career opportunities in science will be more apparent, more stable, and 
more rewarding. 

(k) In addition to sustaining patterns for support of sound 
individual research projects, there will be a marked increase in medical 
research that is organized on a voluntary and collaborative basis. Such 
cooperative endeavors will protect the individuality of the participating 
scientists and at the same time recognize that certain questions can best 
be attacked when a comprehensive, agreed-upon plan exists to explore every 
facet of the problem, using all known approaches and all relevant scientific 
disciplines. 



- 19 - 

(5) There will be Increasing evidence in the patterns of research 
support and in the substance of the work supported, that the urgent 
problems of disease in man must be approached both by free and undirected 
inquiry at fundamental levels and by intensive study of the disease or 
condition itself, seeking leads as to possible means for prevention, 
diagnosis, and treatment despite the absence of knowledge of cause. 

(6) There will be progressive demolition of the geographic and 
political boundaries which limit the ability of science to advance with 
optimum speed and effectiveness. 

(7) There will be significant improvement in the techniques by 
which scientists communicate with each other, with the professions that 
must better understand science in order to use its product, and with the 
people as a whole. As a resiolt, there will be marked improvement in the 
processes by which advances in research are identified and readied for 
application. 

(8) Because better health is a primary public objective, and 
because research is recognized as a way to better health, there will be 
increasing public support of medical research and demand for its effective 
prosecution. Any such positive aspiration of the people takes many forms 
and finds many modes of expression. The normal interplay of these forces 
will cause support of medical research to be maintained in that balance 
between public and private sources which is characteristic of our society. 

Thus, in the long view, there appears to be ample reason to be 
optimistic about the future of medical research. 



- 20 - 
Trends in the substance of medical reseaxch 

It is much more difficult to project trends in the substance of 
medical research. Chstracteristically, it is the unexpected new leads, 
the swift turn of events, the brilliant synthesis of diverse and seemingly 
unrelated findings, that occasion changes in direction and points of 
emphasis in science. And these, of course, cannot be predicted. 

On the other hand, those who plan and administer research programs 
must vmdertake to estimate these things in order to anticipate emerging 
needs in terms of manpower, facilities, and support. 

(1) It seems almost certain, for example, that one of the major 
substantive developments in the years ahead will be related to the in- 
creasing involvement of the physical sciences in the study of biological 
problems. This includes not only the skills, knowledge, and point of view 
of the physical scientist but also the instrumentation and the means for 
quantification of data which have been developed in this field. 

(2) In the same sense, there is growing awareness of the importance 
of the behavioral sciences as part of the total approach to understanding 
biological problems. As research areas are better defined and understood, 
it is evident that the interrelationships among somatic, psychosomatic, 
and psychic illness are close indeed. 

(3) It can be anticipated that medical research in the future will 
give progressively greater attention and emphasis to the environmental 
factors that may be associated with the causation of disease, as well as 
those associated with the positive maintenance of good health. 



- 21 - 

(k) It is probable, too, that stress will be placed on the study 
of population groups — using selected samples, both at home and abroad, 
with striking similarities or gross differences, and studying and manipu- 
lating the variables in an effort to identify the factors related to the 
occurrence or non-occurrence of disease. 

(5) On the other end of the spectrum, science will undoubtedly 
extend and intensify its probings of the very secrets of the life processes 
themselves — of cells and their requirements and the events that cause 
their destruction or uncontrolled proliferation, of macromolecxjilar and 
micromoleculsir particles and their action and interaction. It is one of 
the challenges and frustrations in cancer research, for example, that the 
ultimate understanding of cause may come from study of the smallest known 
particles of organic matter, to large pop^^lation groups with either high 
or low cancer incidence, or anywhere between the two extremes. 

These and other substantive trends in medical research may or may 
not take place. By action, a nation or a family of nations can foster 
conditions which encovirage them to evolve. But in the final analysis, they 
spring from the state of knowledge at any given time, the motivating forces 
of the body scientific, and the insight of science into its responsibilities 
both within itself and to society. 

One irrefutable point emerges. The term "medical research" has won 
widespread and popular usage. It is a good one, in that — like our 
categorical Institutes at the National Institutes of Health — it automatic- 
ally focuses on one of the purposes of research. But it, like so many 
other terms, must be given context for usage. As I use the term, it is 



- 22 - 

not "medical" research in the restrictive sense. It is a blend of the 
biological, physical, behavioral, and social sciences, used as required 
for the better understanding of health and better control of disease in 
man. And it draws upon and supports its full share of fundamental inquiry 
which is not designed to have relevance to any particular field of 
research, but may have. 
Conclusion 

I know the Committee will have reason to be pleased with the 
reports of progress from the Institute Directors and others representing 
the nine appropriation requests which together form the operating programs 
of the National Institutes of Health. 

The past year has been full, challenging, and sometimes difficult 
for all of us. But I feel we have moved ahead on many fronts. The 
reward lies in the degree to which, through the appropriations you make 
to us — appropriations made on behalf of the people and directed to the 
improvement of their health — we are able to meet the present needs and 
enlarge the future capacities of medical science, which does give, and 
can continue to give in ever-increasing measure, life itself. 



ATTACHMENT A 
DIVISION OF BIOLOGICS STANDARDS 
BACKGROUND 

The Federal Government's responsibility for the control of biological 
products began on July 1, 1902, with the passage by the Congress of an Act 
to regulate the sale in interstate commerce of all viruses, serums, toxins, 
and analogous products applicable to the prevention and cure of diseases 
of man. The statute, now included in the Public Health Service Act, is 
basically the same as in 1902, when the technical responsibilities of the 
biologies program were assigned to the National Institutes of Health, 
then known as the Hygienic Laboratory. In 1937^ the Laboratory of 
Biologies Control was created within the National Institutes of Health; 
and in 19^8 it was made a part of the National Microbiological Institute. 
In June 1955^ authority w£is granted the Surgeon General by the Secretary 
of the Department of Health, Education, and Welfare to expand the biologies 
control fimction of the Public Health Service to the status of a 
separate division within the National Institutes of Health, called the 
Division of Biologies Standards. 

GENERAL MISSION 

The primary fvmction of the Division of Biologies Standards is to 
administer the provisions of the Public Health Service Act and Regulations 
pertaining to the safety, purity, and potency of all biological products 
offered for sale, barter or exchange in interstate commerce or for export 
or import. Such products include vaccines, antitoxins, therapeutic serums, 
and human blood and its derivatives. 



- 2 - 

Biological materials are derived for the most part from pathogenic 
or potentially pathogenic microorganisms. Principally for this reason, 
the preparation of these materials requires careful control to minimize 
safety hazards which might occur in the course of processing. In addition 
to safety precautions, control measures are necessary to assure final 
products of satisfactory potency. Effective control requires the designing 
and development of adequate and practical standards for production and 
testing, caref\il surveillance of production methods, and a continuing 
effort to achieve improvements in testing procedures. 

The introduction in the early 19^0 ' s of a new method of producing 
vaccines by growing the microorganisms in embiyonated hens eggs, marked 
the beginning of rapid medical advances in the general area of infectious 
disease therapy. The first of these vaccines were typhus vaccine and 
yellow fever vaccine. Before that time, with the exception of smallpox 
and rabies vaccine, all immunizing agents were produced by classical 
bacteriological methods. In 1955; probably the most significant change 
was initiated when poliomyelitis vaccine was produced with the newly 
developed tissue culture technique. 

These scientific advances have resulted in a vast increase in the 
volume and types of such products being marketed, with an attendant 
major change of attitude and approach in the industry. It has become 
keenly competitive, with manufacturers now engaged in extensive, and very 
costly research programs, each vying for vantage positions through the 
introduction of new and improved techniques. 



- 3 - 

These laxge scale research activities "by industry make it imperative 
for the control agency to keep abreast of the advances constantly developing 
by augmenting its research facilities and maintaining adequate developmental 
research programs. 
Control Activities 

A system of licensing remains the basis upon which the control of 
biological products rests today as it did in 1904 when the first establish- 
ment was licensed to produce smallpox vaccine. 

This system involves the issuing of both establishment licenses 
and product licenses following the determination by the Division that 
prescribed standards for safety, purity, and potency have been met. These 
standards are set forth in regulations which are continually reviewed for 
adequacy in the light of new advances. Additional standards are formulated 
as new products are developed. 

During the past year the first set of specific regulations for a 
blood product became effective with the approval of standards for the 
processing of human whole blood. Prior to that time control of this 
product had been affected by the general provisions of regulations for all 
biological products supplemented by more detailed technical guides pre- 
pared by the Division. With the steadily increasing use of blood and 
blood products these processing methods became stabilized sufficiently to 
warrant their translation into regulations which will also provide a 
foundation for the future development of control measures for other blood 
products. 



- k - 

A total of 270 separate biological products are now licensed. 
These are manxifactirred in l6k licensed establishments for which over 
1100 product licenses are in effect. A major activity of the control 
program related to the extent of this activity is the review of manufac- 
t\irer's records of production and testing and the testing in the 
Division's laboratories of representative samples of these products. 
Tests, ranging from relatively simple sterility tests to complex^ time- 
consuming, costly potency determinations are carried out each year on 
approximately 3^000 individual lots of a wide variety of biological 
products. 

In addition to the inspection of manufacturing facilities and 
procedures prior to the issuance of a license, each of the licensed 
establishments is inspected annually to assure continuing compliance 
with prescribed standards. Supplementary special inspections are 
carried out whenever indicated. Close liaison is maintained with 
representatives of professional and technical staffs of the establish- 
ments involved regarding proposed plans for new facilities and for 
modification of existing structures and equipment devoted to the 
production of biological products in so far as they may affect the 
safety, purity, and potency of these products. 

In order to assure that each manufacturer markets a licensed 
product consistently acceptable and of uniform potency, standard physical 
references preparations axe developed wherever possible and are 
furnished to industry for use in assaying each lot or batch of such 
products, approximately 4,000 vials being distributed annually by the 

Division. 



- 5 - 

The control of biological products has been characterized from 
its beginning by the close cooperation between the Division and the 
manufacturers. Frequent meetings are held between members of the Division's 
professional and administrative staffs and groups of manufacturers who are 
concerned with common problems. In addition, from I50 to 200 conferences 
are held each year with technical representatives of individual manufacturers 
who desire to discuss with members of the Division staff production and 
testing problems peculiar to their own organization. 

Through such close cooperation with the technical representatives 
of industry as well as with independent investigators throughout the 
Nation the Division is frequently able to identify potential problem 
areas in biologies production and control before serious difficvilties 
ari se . 

Division scientists, serving as members of international study 
groups, have taken an active part in the World Health Organization's program 
for the development of international \iniformity of biological products. 
This year, international recommendations, based on United States experience, 
were developed for poliomyelitis vaccine by one WHO study group, and 
recommendations for yellow fever and cholera vaccines by another group. 
Adoption of such requirements by national control authorities for these 
and other vaccines will serve to promote world-wide improvement and 
uniformity of these products, and will permit the free exchange of such 
substances between Nations in times of emergency. 



- 6 - 

Research Activities 

The control program of DBS is necessarily supported "by an active 
research program which enables the Division to keep abreast of the 
developnent of new and improved immunizing agents and to prepare physical 
references as well as testing procedures for these products once they are 
ready for commercial production. 

This year, as the procedures for the production and control of 
poliomyelitis vaccine became stabilized, and the current problems of 
influenza vaccine were met, the Division's research efforts were directed 
toward investigations in other fields of importance, one of which was the 
complex problem of live virus vaccines. 

A test using the test tube instead of living monkeys has been 
studied which helps to differentiate between virulent and attenuated 
poliovirus. The poorer growth of attenuated poliovirus strains in 
continuous live monkey kidney cell tissue cultures has been shown to be 
in agreement with their low degree of virulence in living monkeys as judged 
by their effect on the central nervous system. The Division is planning 
to use this technique to determine the genetic stability in human beings 
of the attenuated polioviruses now being considered and studied by 
independent investigators for use in living poliovirus vaccines. 

As tissue culture methods become applicable to the production of 
further vaccines, and as the supply of monkeys becomes more limited, 
investigative work on substitute tissue cells is increasingly important. 



- 7 - 

A simplified method of measuring the potency of poliomyelitis 
vaccine in a quantitative manner using chicks instead of monkeys, which 
has been \ander intensive study by DBS scientists for the past two years, 
has now been perfected. A collaborative study with industry in 1957 showed 
that the baby chick was a promising test animal; monkeys have been used thus 
far. During the past year, vaccine manufacturers and the DBS have used 
the chick potency test concurrently with the monkey potency test on a 
trial basis. Data on the relative merits of the two tests now indicate 
that the chick test provides reliable measures of potency for all three 
vaccine strains and is a less complex assay procedure. It is anticipated 
that this test will replace the monkey potency test early in 1959' 

DBS scientists have also developed a test-tube potency test for 
poliomyelitis vaccine, based on the observation that antibodies will 
combine with either virus or vaccine. The test is a valuable addition to 
the techniques available for testing the vaccine's antigenicity in that 
it is simple, economical, and reproducible from one test to the next as 
compared with the animal potency tests. 

>feans of extending the range and sensitivity of the monkey safety 
test for poliomyelitis vaccine are under study and results using a method 
of concentration of the vaccine prior to injection into the monkeys are 
promising. 

With the growing desire for multiple antigen preparations so that 
children can be immunized against diphtheria, tetanus, whooping cough, and 



- 8 - 
poliomyelitis simultaneously, research to determine the possible effect 
of such combinations on the safety, purity, and potency of these products, 
as well as the suitability of existing testing procedures is essential. 
Adequate control of such miiltiple products frequently requires the 
development of new testing procedures and the modification of required 
standards. The Division has been working closely with the manufacturers 
in this respect. 

The Division has continued to utilize the assistance of the 
Technical Committee on Poliomyelitis Vaccine and to maintain close 
cooperation with the technical representatives of industry, giving 
attention to problem areas, both actual and potential. As a result, 
changes designed to improved the vaccine, continued to be introduced. 

While the problems inherent in the testing and clearance of over 
61 million doses of the monovalent and polyvalent Asian strain vaccine 
were met by January 1958^ manufacturers continued to produce the poly- 
valent influenza vaccine. By October 15, 1958, 73 lots of this vaccine 
had been cleared for release, representing a gross vol\ime of approximately 
12 million doses. Potency determinations of the vaccine based on the 
mouse antigenicity test have been reinstated. 

Keyed to the possible production of a measles vaccine in the near 
future, studies relating to the eventual preparation of a standard 
reference reagent as well as the standardization techniques appropriate 
for the effective evaluation of such an immunizing agent are under way. 



- 9 - 
Collaborative work is also being carried out with other research and 
development laboratories in the development and testing of experimental 
measles vaccines. 

Work on the standardization of gamma globulin for measles antibody- 
content is also being pursued so that it can be used more effectively in 
the control of measles epidemics. 

Continuing studies on the standardization of smallpox vaccine 
using cell culture methods have developed evidence that primary rabbit 
kidney cells provide a sensitive and reproducible techniques for the 
measurement of the viral content of the vaccine. Collaborative studies 
with other laboratories are presently being conducted to determine the 
correlation of this method of potency testing with the present titration 
method. As a result of improvement in laboratory methods^ fvirther studies 
are being maxie to compare clinical tests of potency with results obtained 
in laboratory animals. This work is also being applied to a study of the 
stability of dried smallpox vaccine with other laboratories interested in 
the problem. 

DBS scientists are actively participating in a study sponsored by 
the National Research Coimcil of various forms of plasma products that 
would provide safe and relatively inexpensive blood volume expanders for 
defense agency stockpiling. One of the principal problems in the processing 
of plasma preparations in which the Division is vitally interested is the 
inactivation of the agents of serum and infectious hepatitis. Results 



- 10 - 
indicate that the new preparations are not suitable for stockpiling at 
this time because of protein changes of unknown clinical significance 
or because of a lack of experience to support shelf -life and salvage 
value. 

The long term study of the effects of conditions of storage on 
albumin started four years ago indicates that changes occur in liquid 
albumin stored at ambient temperatures. These studies will provide a 
basis for recommendations for attaining a maximum storage life for al- 
b\miin in the emergency stockpile. 

Studies of long term preservation of red blood cells have served 
as a basis for establishing a bank of extremely rare bloods for emergency 
use. The blood with added glycerine is stored at -45°C. and probably 
can be stored for 3 or more years. This application of fimdamental 
research to the practical problem of extending the storage period of 
blood clearly indicates the feasibility of the methods but more work must 
be done to reduce the labor required in processing. 

Studies were completed and reported this year on a cross-match 
pilot tube. The new tube maintains an sidequate pilot sample of blood, 
intended for transfusion^ for at least a month. This paves the way for 
increasing the storage period for whole blood for transfusion. 



^ yji-c^ c<Y^ 



SUMMARY OF OPENING STATEMENT 

Chief, Division of General Medical Sciences, 
National Institutes of Health 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"General Research and Services, Public Health Service" 



Mr. Chairman and Members of the Committee: 

This concerns the research and training grants portion of the 
General Research and Services Appropriation, which constitutes the 
i960 program proposals of the newly created Division of General Medical 
Sciences. 

The establishment of the Division was approved by Secretary Folsom 
on July 16, 1958. The Division provides a new organizational framework 
for administering the program of non-categorical research and training 
grants, providing fellowships for general research training, conducting 
studies and promoting research relative to general medical research and 
training needs, and directing the Center for Aging Research. 

The budget for these programs has grown from $5 million in 195^ to 
$25^^25,000 proposed in the I96O President's Budget. Programs will support 
new research and training in basic sciences, public health and medical 
care- -growing problems which cannot adequately be met through the 
disease-oriented categorical programs of the Institutes. The Division 
also provides a center for coordinating research and training activities 
in broad cross-categorical areas--such as aging. 



- 2 - 

The progress we make in clinical and applied medical research 
ultimately depends on fundamental research in basic areas. The findings 
and observations of scientists, supported in part by non-categorical 
research grants, have added significantly to the sum of knowledge 
necessary to the later solution of problems related to disease processes. 
It will be of interest to the committee that we are now supporting eleven 
research projects in foreign countries including a $300,000 grant to the 
World Health Organization to investigate those areas in international 
health research which can be intensified and expanded. 

The lack of research-trained manpower is a limiting factor in the 
conquest of disease and the accumulation of new knowledge in basic medical 
and biological fields. These problems require broad action, otherwise the 
pace of fundamental and applied research and clinical medicine will be 
hampered. Training funds were increased from $2,962,000 in 1958, to 
$6,OliO,000 in 1959> permitting, among other things, the establishment of 
additional training programs. By the end of this year 170 research 
training programs will have been established as compared to 75, in 1958. 
The Research Fellowship Program is expected to continue at its 1959 level 
of $3,260,000, supporting Regular, Postsophomore, Foreign, Part-time and 
Senior Research Fellowships. 

The Center for Aging Research which was established in 195 6 has 
been transferred to the Division from the National Heart Institute. This 
group stimulates and coordinates research and training in gerontology 



- J - 

through both grants and direct research by all Institutes. The total 
National Institutes of Health support of projects relating primarily 
to gerontology vas over $2 million in calendar year 1958 and 
$^^33^980 in 1959' Noteworthy accomplishments of vork in aging 
include the establishment of the interdisciplinary research project 
at Duke University, which was reported to this committee last year, 
and a second similar project at the Albert Einstein College of Medicine, 
which was approved by the Surgeon General in April 1958. The Center 
for Aging Research plans to stimulate further inquiry into three broad 
areas: (l) behavioral and social sciences; (2) the clinical sciences; 
and (3) the biological sciences. 



OPENING STATEMENT 

Chiefs Division of General Medical Sciences^ 
National Institutes of Health 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"General Research and Services^ Public Health Service" 



Mr. Chainnan and Members of the Committee: 

I am pleased to appear before you for the first time on behalf 
of the research and training grants portion of the General Research 
and Services Appropriation, which constitutes the I96O program proposals 
of the newly created Division of General Medical Sciences. The other 
major division included in this appropriation, the Division of 
Biologies Standards, has been discussed by the Director, National 
Institutes of Health in his opening statement. 

On July 16, 1958^ Secretary Folsom approved the establishment 
of the Division of General Medical Sciences. The new Division admin- 
isters the National Institutes of Health program of non-categorical 
research and training grants, provides fellowships for general 
research training, conducts studies and promotes research relating 
to general medical research and trainlug needs, and directs the Center 
for Aging Research at the National Institutes of Health. 

The nucleus of this new Division is comprised of the general 
research and training programs transferred from the Division of 
Research Grants, and the Center for Aging Research transferred from 
the National Heart Institute. 



- 2 - 

'The Division was established to provide a new organizational 
framework for the conduct and continued development of basic non- 
categorical research, training and fellowship programs encompassing 
general medicine, public health, aging, and clinical and pre-clinical 
sciences supported through the General Research and Services appropri- 
ation. The budget for these grant programs has grown from a level 
of $5,000,000 in 195 6 to a total of $25,^25,000 proposed in the 
President's Budget for 1960 which is an increase of $788,000 over the 
1959 obligation plan. These programs will support new developmental 
and exploratory research and training activities in the basic sciences 
and in problems of public health and medical care services. These 
are areas of growing importance which cannot be adequately developed 
through the disease-oriented categorical programs of the Institutes. 
As research, progrems in these basic areas develop to the point of 
having importance for specific disease entities, support for them is 
in many cases ass\jmed by the categorical Institutes. 

The Division also provides a center for the coordination of 
research and training activities directed toward broad cross- 
categorical problems, such as fostering research and training on 
aging through the Center for Aging Research. 

During 1959, the research and training grants of a non- 
categorical nature are being greatly expanded, thanks to the interest 
of this Committee and the Congress. The backlog of approved research 
grants applications in the general area v/hich has existed for several 



- 3 - 
years has been substantially reduced, the senior and foreign fellov;- 
ship programs are being accelerated; and the increases appropriated 
for the general research training program are serving to stimulate 
and expand the training programs in the areas of basic biological, 
medical and health related sciences, and in other specialty areas 
where acute shortages of research- trained manpower exist. 

I should like to present in more detail some of the aspects 
of our program to illustrate our current activities. 

RESEARCH GRANTS 

The research projects supported by the Division of General 
Medical Sciences are for those areas that are not covered by any of 
the programs oriented toward specific kinds of disease process. They 
include fundamental medical and biological research, research in 
problems of public health, including environmental health, and research 
in aging. 

The progress we make in clinical and applied medical research 
ultimately depends on the fundamental investigations in basic areas. 
The findings and observations of scientists supported in part by 
general, non- categorical research grants have added significantly to 
the sum of knowledge necessary to the later solution of problems 
related to disease processes. 



- k - 

A good example of how such a grant has led to important 
findings in a fundamental area is reflected in the isotope studies 
of Drs. p. D. Boyer and M. P. Stulberg at the University of Minnesota. 
By tracing the metabolic pathway of isotopically labeled amino acids 
in bacteria^ they have discovered new clues as to how these 
substances become the "building blocks" of protein. These grantees 
have used a new approach to the important problem of hov; cells 
synthesize proteins. By feeding isotopically labeled amino acids 
to bacteria, they have been able to deduce important information 
about the pathway of incorporation of amino acid into protein by 
measurement of what happens to oxygen atoms that are lost from 
amino acids when protein is made. 

Another example is the work of a group of the Division of 
General Medical Sciences grantees at the University of Missouri who 
are studying a food problem that currently presents a dilemma. 

Cyclical shortages of food and high costs of spoilage make 
it necessary to investigate extensively those methods that increase 
the "shelflife" of perishable foods. Recently, much experimental 
study has revealed antibiotics to be highly successful agents for 
food preservation. Although this promises to be a solution to the 
problem of how to retard food decay, it presents possible public 
health hazards such as the emergence of resistant organisms which 
are potentially pathogenic for human beings. 

In a series of papers the grantees have demonstrated that 
one commonly used antibiotic, streptomycin, retains its activity 



- > - 

after being cooked^ that another antibiotic^ oxytetracycline^ can be 
detected in cabbage even after being processed to cole slaw^ and that 
animals fed streptomycin residue harbor streptomycin-resistant coliform 
bacteria. 

The possible health hazards due to the emergence of antibiotic- 
resistant microorganisms resulting from antibiotic preservatives are 
a matter of concern not only to the Federal Government but among those 
who seek to extend the use of antibiotics to preservation of many other 
perishable foods. 

A substantial increase in general research grant funds vas 
appropriated in 1959 to reduce the backlog of approved applications 
which has existed for many years. These additional fimds will increase 
the number of grants in this area from 713 i^i 1958 to approximately 
1;100 in 1959" The I960 increases will bring the total number of 
grants supported to approximately 1,150. 

TRAINING GRANTS 

Lack of research-trained manpower is a limiting factor in the 
conquest of diseases and the accumulation of new knowledge in the 
basic medical and biological fields. Unless this paramount challenge 
is successfully met in the near future, the pace of research in these 
fields as well as in clinical medicine will be materially hampered. 
The General Research Training Grant program has the primary 



- 6 - 
responsibility for stimulation and expansion of research training in all 
fundamental sciences related to medicine and health and in other special 
areas not appropriately the concern of the categorical Institutes. 

For a number of years, outstanding medical educators and other 
members of the scientific community have warned that markedly increased 
numbers of younger scientists and physicians must be interested in and 
trained for careers in all branches of academic medicine and biology if 
we are to keep up the current pace of research and suitably staff our 
research institutions and new medical schools. 

The increase from $2,962,000 in I958 to $6,040,000 in 1959 has 
served to stimiilate and expand this program in the areas of basic 
biological, medical and health related sciences, by assisting in the 
establishment, expansion, and improvement of training programs in 
universities and other research institutions. 
Experimental training grant program 

The experimental training grant program has permitted 13 of our 
foremost medical schools to establish experimental training programs. 
These grants aid the schools in the various means of identifying and 
giving special research training to selected, highly motivated medical 
students to stimulate their interest in medical research and careers in 
academic medicine. The experimental training grant program was started 
in 1957. The $500,000 requested for I960 will permit the continuance of 
these training grsmts. 



- 7 - 
Training grants in "basic medical and biological disciplines 

By the close of 1959, 170 research training programs will have 
been established, an increase of 95 over 1958. These programs provide 
good geographical dispersion and timely support for several unique 
research training facilities. In addition to making training available 
to more students, the new training programs also serve to increase the 
rate of production of trained personnel. A factor contributing to the 
present shortage of trained personnel is the extended time required to 
complete graduate studies. In order to support themselves, students 
must work as part time research or teaching assistants, and thus must 
spread their graduate studies over 5 to 7 years. The support offered by 
stipends will cut this time to 3 to 4 years. In addition the 
accelerated turnover will free the much needed space and facilities for 
the use of other students. 

Six new training grant committees will review and evaluate training 
grant applications in many basic science areas including anatomy, genetics, 
biochemistry, pathology, pharmacology, and physiology. 

RESEARCH FELLOWSHIPS 

The research fellowship program of awards to individuals is 
complementary to the training grant awards to institutions. It is 
anticipated that support for 196O will continue at the 1959 level of 
$3*260,000. Five major areas are provided for in the program: 



- 8 - 

(1) Regular research fellowships - These awards are for the 
research training on a f\ill time "basis of scientists at the predoctoral, 
postdoctoral, and special levels, for careers in the fiindamental fields 
of the "biological sciences such as genetics, "biochemistry and physiology. 

Predoctoral research fellowships emphasize research training in 
fundamental "biological fields from which research findings serve to advance 
these sciences generally and may have application to specific diseases or 
categorical fields. Postdoctoral research fellowships are awarded to 
selected, promising holders of the Ph.D., D.Sc, D.D.S., M.D., and Dr. P.H. 
degrees who are interested in undertaking advanced research training 
related to a career in the health sciences. Special research fellowships 
are awarded to accomplished researchers who require fiirther training or 
knowledge of new techniques or disciplines in order to increase their 
research productivity and to "broaden their fields of scientific interest. 

In 1958^ 67 regular fellowships were awarded; approximately 35 
will "be awarded in 1959; and the program is planned to continue at 
approximately the same level in I96O. The decrease in regular fellow- 
ships was made necessary "by the expanded program in foreign fellowships. 

(2) Post- sophomore research fellowships - Through these grants, 
superior medical and dental students have an opportunity to obtain one 

to three years of research training prior to completion of their professional 
degrees. In general these fellowships are awarded to candidates at the 



- 9 - 
iiat\iral break between their preclinical and clinical course work. In 

1958, 117 postsophomore fellows were awarded and I3I are being awarded in 

1959* The program for 196O is projected at the same level as that for 

1959. 

(3) Fellowships for scientists in other countries - These fellow- 
ships are designed to develop more extensive and effective international 
exchanges of people and ideas in the medical and biological sciences. 
The number of postdoctoral fellowships was increased from 17 during 1958 
to 38 fellowships representing expenditures of $3ii-5,00O during 1959. 
The i960 program is expected to continue at this level. 

Recipients of these fellowships are encouraged to spend a short 
time at the IJational Institutes of Health to become acquainted with our 
facilities and to give the National Institutes of Health the benefit of 
their technical competence. The remainder of their year's study is at an 
outstanding medical research center, thus providing the opportunity to 
exchange research ideas and techniques with outstanding scientists in the 
United States. The exchange of ideas, information and points of view 
is mutually beneficial to our scientists and to those from other countries. 
It has the further benefit of giving foreign scientists a more realistic 
concept of the research and training conducted in this country. 

(h) Senior research fellowships - The senior research fellowships 
program is designed to help relieve the shortage of researchers and 
teachers in the preclinical departments of medical, dental, and public 



- 10 - 
health schools. These awards provide an incentive to competent investi- 
gators to remain in research rather than to move into the more highly 
remunerative clinical fields. 

The increase from $1,000,000 in 1958 to $2,000,000 in 1959 will 
increase the number of preclinical science investigators from 86 in 1958 
to approximately 172 in 1959* In 19^0, this program will continue at the 
1959 level. 

(5) Pa rt-time student fellowships - The early stimulation of 
research interest in promising students has proved to he the most fruitful 
method of promoting a continuous flow of highly motivated and selected 
recruits into the medical, public health, and nursing research fields. 
It serves to increase the number of full-time researchers in the related 
basic fields. In addition, it assures an increased nxomber of physicians 
and others with research orientation who can better apply basic research 
findings on clinical levels. 

In 1958, 3^0 students received part-time fellowship awards, and 
we plan to continue the program at the same level in 1959 and I96O. 

THE CENTER FOR AGING RESEARCH 

The Center for Aging Research was established in 1956 and adminis- 
tratively located in the National Heart Institute. In July I958, this 
activity was transferred to the newly created Division of General Medical 
Sciences, 



"U:": ":■ 



- 11 - 

This group serves to stimulate and coordinate research and training 
in gerontology through both grants and direct research in this field by 
all of the Institutes. Total National Institutes of Health support of 
research projects classified as relating primarily to gerontology was 
$i+6i4-,000 in 1957^ and $1,779,000 in 1958. In 1959 support of research 
in aging will probably approach $2,000,000. 

In addition to the large interdisciplinary research project in 
aging at the Duke University Medical School (which was reported to this 
committee last year) a second similar project was developed at the Albert 
Einstein College of Medicine with staff assistance from the Center for 
Aging Research. In April, 1958, the Surgeon General formally awarded the 
$2,000,000 grant for this five year project, which is supported by the 
National Heart Institute, the National Institute of Mental Health, and 
the National Institute of Arthritis and Metabolic Diseases. 

Since the study of aging is an area that embraces many disciplines, 
the multidiscipllnary collaborative approach holds much promise. The 
Center is actively encouraging and assisting high caliber researchers, wbo 
are interested in the study of aging, to organize and operate inter- 
disciplinary programs in universities and medical schools. These programs 
cut across traditional departmental barriers and facilitate the exchange 
of information between individuals with different backgrounds. 



- 12 - 
The Center plans to stimulate further inquiry into three "broad 
areas : 

(1) The behavioral and social sciences - where individuals who 
are trained to conduct research on problems in these sciences will be 
encouraged to study the changing social structure and the place of the 
older individual. Also, the older worker's response to an increasingly 
complex technology should be assessed. Fiorther, much more should be 
learned about the mental health aspects of retirement. 

(2) The clinical sciences are confronted with the problem of 
chronic disease. Factors which predispose to the development of chronic 
disease as a result of aging must be sought. Methods which will allow an 
assessment of the degree of benefit a debilitated individual may receive 
from available rehabilitation procedures should be devised. Also, there 
is need for further investigation into how the cost of rehabilitation 
can best be met. 

(3) The biological sciences during the past decade and a half 
have shifted research techniques in large measure from the microscopic 
to the submicroscopic level. Biochemists, biophysicists, and investi- 
gators in other disciplines will be urged to study age changes in matter 
and energy at the most basic levels, where the origins of the aging 
process most likely rest. 



- 13 - 

smmARY 

The new Division of General Medical Sciences is pleased to report 
on the progress it has made in carrying on the basic non-categorical 
research, training and fellowship programs d\aring 1958* The transfer of 
these activities from the Division of Research Grants was made with no 
interruption to these programs during a period of rapid growth. The 
research activities of universities and other research institutions 
throughout the country have benefited from the Division's increased re- 
search grant program, and the backlog of approved grants has been reduced 
substantially for the first time in many years. There has been greatly 
increased activity in the training and fellowship programs which will 
enlarge the supply of research- trained manpower. It is our hope and 
expectation that the knowledge gained from basic research and from the 
increased numbers of better trained investigators ultimately will be 
reflected in better health for all people. 

The Division of General Medical Sciences has given and will 
continue to give special attention to those areas recommended by this 
committee. 



SUMMARY OF OPENING STATEMENT 
by 
Director, National Cancer Institute, 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"National Cancer Institute" 



Mr. Chairman and Memhers of the Committee: 

The activities of the National Cancer Institute continued to 
expand in the past year, reflecting a general increase in the scope of 
cancer research throughout the United States and abroad. Plans for 
i960 call for a budget of $75,218,000 to finance these endeavors which, 
including the comparative transfer, is the same as the 1959 appropri- 
ation, but $2,i+07,000 greater than the 1959 obligation plan. The 
mounting international character of cancer investigation was amply 
illustrated by the successful Seventh International Cancer Congress, 
which met last July in London and was attended by some 2,500 members 
from 63 nations. 

Among the most important research accomplishments of the year 
were the new discoveries pertaining to the cancer-virus relationship. 
Institute scientists collaborating with investigators of the Division 
of Biologies Standards reported that an agent that causes multiple 
tumors in mice is unquestionably a virus, and that it also induces 
neoplasms in rats and hamsters. Further, the scientists developed an 
imm\inizing agent 97 percent effective in preventing the growth of 
tumors in hamsters challenged with the virus. 



- 2 - 

A group of outstanding scientists recently assembled at the 
National Institutes of Health to discuss virus-cancer research and 
recommend steps to facilitate additional, fruitful work in this area. 
They agreed there is need for more basic virus research, for improved 
instrumentation, for greater availability and distribution of living 
host and virus materials, and for training of biologists, zoologists, 
and chemists in fields related to the virus-cancer problem. 

A virus research section has been established in the Laboratory 
of Biology to strengthen investigations at the Institute, and the 
National Advisory Cancer Council has recommended that the grant mecha- 
nism be modified to provide long-range, interdisciplinary support of 
research, which could be valuable for further progress in the virus 
area. 

Plans for a comprehensive diagnostic research program are being 
formulated, and an ad hoc committee of scientists from such fields as 
biology, pathology, and electronics has met with members of the staff to 
discuss the possible course of such a program. It is contemplated that 
the diagnostic program will be carried out under grants, contracts, and 
direct operations. Other significant developments in cancer detection 
are: successful field trials with the cytoanalyzer j promising initial 
results in an attempt to develop a cytologic test to detect malignant 
cells in circulating blood; and establishment of a unit in the Bureau 
of State Services to apply the cytologic test for uterine cancer to 



- 3 - 
the general population. The Institute is continuing cytology research 
particularly in an effort to apply the test to the detection of cancer 
of other hody sites. 

inae program of the Cancer Chemotherapy National Service Center 
is now in full operation. Clinical studies of some 70 anticancer agents 
are in progress in 175 to 200 hospital services throughout the country. 
Contract research constitutes a major part of the program^ the role 
of private industry is increasing and is expected to expand further as 
a result of the adoption of a liberalized Departmental patent policy 
relating to chemotherapy contracts. 

Within the year, important research findings were reported in the 
fields of cancer causation, characteristics, and therapy. Staff 
scientists and grantees have investigated the complex problem of lung 
cancer etiology and have presented significant new data on the role of 
smoking, air pollution, occupational hazards, and other factors. 
Notable among reported studies of cancer characteristics were investi- 
gations of the properties of two strains of mouse cells, derived from a 
single cell, that differ markedly in their capacity to grow as tiJimors 
when injected into mice of the original strain. Studies on metastasis 
and on water soluble diets also contributed valuable information on the 
nature of cancer. 

Research on cancer therapy again produced a niomber of significant 
and encouraging developments. Studies in animals and in the clinic pro- 
vided encouraging new leads that could hasten the development or more 
effective, perhaps curative, drugs for the treatment of cancer. 



! i 



OPENING STATEMENT 
by 
Director, National Cancer Institute 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"National Cancer Institute" 



Mr. Chairman and Members of the Committee: 

Since I last came before this Committee to review the activities 
of the National Cancer Institute, we have witnessed a substantial 
increase in the scope of cancer research. The Congress has been respon- 
sive to the increasing need for expanded work in this field and has made 
it possible for the National Cancer Institute to continue, and in some 
cases to augment, its comprehensive program. Our plans for I960 call 
for an appropriation level of $75,218,000 which, including comparative 
transfer, is the same as 1959, but $2,^07,000 greater than the 1959 
obligation plan, 

A great deal of valuable new information on the complex problem 
of cancer has been gained through the efforts of scientists throughout 
the United States and abroad. One of the best illustrations of the 
worldwide activity in cancer investigation was the very successfial 
Seventh International Cancer Congress, which met last Jvily in London. 
More than 2,500 members representing 63 nations attended the meetings 
and heard papers presented by some of the world's outstanding cancer 
investigators . 



- 2 - 

Another new development affecting cancer research is the steadily 
increasing level of cooperation between the Federal Government, inde- 
pendent research scientists and institutions, the academic world, and 
American private industry. This is best illustrated in the operation 
of the national cancer chemotherapy program, but it is also important 
of other areas of the study of cancer and in medical science generally. 

An additional, significant development in this field is the 
strengthening of the Cancer Control Program in the Bureau of State 
Services to which the National Cancer Institute provides technical 
guidance and assistance. This staff has the responsibility of 
encouraging and aiding the prompt application of new knowledge and 
techniques by private physicians and public health and allied workers 
throughout the country. Priority is being given in this program to 
promoting the broader use of the cytological examination for cancer 
of the cei-vix so that the possibility that we now have of substantially 
eliminating deaths from this cause may be achieved as soon as possible. 

Thus, I believe that we are now in a new era of cancer research, 
one in which we can anticipate much progress toward the control of 
malignant disease. The National Cancer Institute, with the guidance 
provided by this Committee, is continuing to take a leading role in 
the quest for new knowledge of cancer. Our intramural and extramural 
research programs, now at their most active level, are producing im- 
portant results in the numerous scientific disciplines that comprise 
cancer research. 



- 3 - 

I should like now to report to the Committee some highlights of 
the year's activities of the National Cancer Institute. I have organized 
my remarks under three general headings reflecting particiilar areas of 
research in vhich the Committee has manifested special interest. These 
headings nr&: virus studies, diagnostic tests, and cancer chemotherapy 
research. In addition, I shall describe several other important pieces 
of research that appear to be highly significant. 

VIRUS RESEARCH 

Last year, I reported to the Committee some truly exciting 
results of investigations into the relationship of viruses to cancer. 
National Cancer Institute staff scientists, working in productive 
collaboration with investigators in the Division of Biologies 
Standards, had succeeded in producing a variety of tumors in mice by 
injecting them with an agent that appeared to be a virus. Within the 
past year, this group of investigators has carried their studies further 
and reported in the scientific literature some most interesting results. 

The agent now has been shown beyond question to be a virus, 
which produces malignancies not only in mice, but in rats and hamsters 
as well. In other words, it has the remarkable property of causing 
tumors in genetically unrelated types of animals. More recently, these 
scientists were successful in developing an immunizing agent that is 
97 percent effective in preventing the growth of tumors in hamsters 
challenged with the virus. This work obviously is of far-reaching 



. k - 

significance, because it provides valuable information on the virus- 
tumor relationship, and because it will undoubtedly stimulate 
additional research. 

This raises the question: How can virus-cancer research be 
piarsued and acceleirated in the most productive and efficient fashion? 
Within the past few months, a group of outstanding scientists from the 
fields of virology, biochemistry, pathology, immunology, cellular 
biology, and biophysics met at the National Institutes of Health to 
discuss the present status of virus-cancer investigations and to make 
recommendations for the future conduct of these important studies. 

The scientists agreed that there is a need for much additional 
basic research to provide detailed information on viruses themselves 
and on the hosts, including man. Tissue culture was cited as a f\mda- 
mental tool for such research as were electron microscope studies and 
investigations utilizing model tumor systems with reference to man. 
The group recognized the need for additional training of biologists, 
zoologists, and chemists in fields related to the virus-cancer problem. 
Further, it recommended that some means be sought to improve the 
availability and distribution of living host and virus materials for 
use in research. 

At the National Cancer Institute, we are now taking steps to 
expand virus research both within the intramural framework and extra- 
murally through the grants program. A virus research section has 



- 5 - 
been created in the Laboratory of Biology in order to strengthen 
investigations of this kind at the Institute. Furthermore the National 
Advisory Cancer Council has recommended that research grants be awarded 
to support large-scale, interdisciplinary explorations over long periods 
of "tinie^ which could be extremely valuable for further progress in virus 
research. 

This problem, like others in the cancer field, is difficult 
because it deals neither with particular fields of investigation nor 
with single biological entities, but with biological, biochemical, and 
biophysical interaction of tliree intimately associated elements: virus, 
cell, and host. Thus, the primary hurdle to be crossed is to identify 
and explain the nature of this interaction. 

Without attempting to probe deeply into the complexities of 
cancer-virus research, let me just mention a few of the questions for 
which adequate answers are lacking. If we assume that all cancers 
result from virus infection, does this mean that viruses cause cells to 
multiply and thus increase the production of variant cells less sus- 
ceptible to growth control, or does the infection affect the growth 
control mechanism itself leading to the overproduction of altered cells? 
Does the cellular alteration represent a response of the cell to inter- 
action of virus conditioned by environmental factors, or does it signify 
the transduction, or passage, of virus material from a malignant cell 
to a normal one? It is apparent that we are not dealing with a 



- 6 - 

particular problem in virology or cancer biology, but rather with a 
host of problems whose solution will only be found through arduous, 
intensive, and often frustrating research. 

Quite naturally, as more and more knowledge is accumulated on 
the role of viruses in cancer causation we can anticipate a growing 
interest in the possibility of developing an anticancer vaccine, similar 
perhaps to the Salk vaccine. Development of the polio vaccine was based 
essentially on an oM and simple formula; find the virus, associate it 
causatively with the disease, produce a vaccine. In the case of polio, 
it was possible to apply this fonaula in a reasonable time with a 
comparatively small amount of basic research, small in comparison with 
the vast accumulation of information already available from cancer 
research. Nonetheless, with respect to polio the result is a vaccine 
that works, although how it works is not completely understood. The 
same formula might be applicable to cancer viruses, including those 
that may be associated with human cancer. With cancer viruses, however, 
the vast majority of the prerequisite fundamental research has not been 
accomplished. 

The select group of scientists who gathered at National Institutes 
of Health to discuss cancer-virus research agreed that such studies may 
lead to a major advance in human cancer research. We are enlisting the 
aid of a number of eminent virologists who will advise us in formulating 
a program of virus-cancer research, I am glad to say that some of the 



- 7 - 

scientists who were most active in the polio research effort have 
decided to apply their talents to the study of malignant disease, and 
will undoubtedly make significant contritutions in this important field. 

DIAGNOSTIC TESTS 

By the use of presently available diagnostic means, it is 
difficult to detect most forms of cancer at their earliest, most 
localized, symptom-free stage. Yet, according to most authorities, 
if there is to be substantial improvement in the cancer cure rate, it 
is necessary that the disease be diagnosed as early as possible and 
then effectively treated. 

Even a casual examination of the scientific literature for the 
past few years reveals that comparatively little investigation has 
been aimed at the problem of early cancer diagnosis. Perhaps this 
results from the belief that improvement in diagnosis could be achieved 
only after some significant differences were found between noirmal and 
malignant cells. Yet, the experience to date gained through the 
application of exfoliative cytology to the detection of uterine cervical 
cancer seems to indicate that we, perhaps, need not await the accumu- 
lation of additional fundamental knowledge of cancer before we attempt 
to develop new diagnostic procedures. 

There is now a large enough body of scientific infoimation, 
based on clinical studies and animal research, to suggest certain 
approaches to this problem that warrant careful study. Furthennore, 



- 8 - 

there are certain research tools, instruments, and techniques that ve 
feel lend themselves readily to investigation of new approaches in 
cancer diagnosis. 

The National Cancer Institute is presently developing prelimi- 
nary plans for a program of diagnostic research along what we believe 
to he sound lines. I should like to sketch briefly the form we feel 
such a program ought to take. 

The approach to this problem will undoubtedly be quite broad in 
scope because of the many scientific disciplines that must be brought 
to bear on it. As we now envision it, the research will proceed along 
four major lines: (l) the measurement of some product of malignant 
growth; (2) the measurement of some bodily change produced by cancer; 
(3) the measurement of some change in the body that favors the develop- 
ment of cancer; and (k) the development of instruments that may 
facilitate the identification of cancer by mechanical, physical, 
electronic, or other means. 

We anticipate that this research will be carried out under 
grants, contracts, and direct operations; and we expect that any 
positive results that may be achieved must still be a nianber of years 
in the future. 

As an initial step in the creation of a diagnostic research 
prograra members of our staff have met with ad hoc committees of 
scientists from such fields as biology, biochemistry, endocrinology, 



- 9 - 
|»atliology^ tissue culture, radiology, and electronics to discuss 
techniques and methods in their respective areas that seem to merit 
investigaition with respect to cancer diagnosis. These meetings should 
serve to spark an interest on the part of some of the participants and 
stimulate them to enter directly into the diagnostic studies field. 
Moreover, the recommendations suggested by participants at such meetings 
could lead to the initiation of research projects supported either hy 
grants or contracts. 

Of course, I am talking now ahout a program that is still in 
the cradle, so to speak, I would not attempt to say what course a 
diagnostic research program of this kind will take. Developments in 
cancer research, both basic and clinical, could alter radically our 
future needs in the axea of cancer diagnosis. At present, however, 
we feel that this is a field worthy of carefully directed, planned 
investigation. A special report on the diagnostic research program 
is being submitted separately. 

This past year has brought several other important developments 
in cancer detection and diagnosis that we consider to be most 
encouraging . 

I have described to this Committee in past years our efforts to 
develop the Cytoanalyzer, an electronic device designed to speed the 
examination of specimens obtained in the cytologic test for uterine 
cervical cancer. I can now report that this instrument has been found 



- 10 - 
to "be capable of accurately selecting a significant percentage of 
specimens that need not te examined further "by cyto-technicians or 
pathologists. The Cytoanalyzer has, therefore, the potential of "being 
useful in the application of the cytologic test among large groups of 
women. This means, of course, that it may help to alleviate the need 
for additional qualified cytotechnicians who are in short supply. 

Still more improvement of the Cytoanalyzer needs to be made. 
We think, for instance, that its accuracy can he improved, that more 
of its operations can he made automatic, and that it can be modified 
for use in the examination of cytologic specimens obtained from other 
parts of the body. I am confident that continued improvement of the 
Cytoanalyzer, coupled with advances in the cytologic technique for 
cancer detection, will provide medical science with a powerful weapon 
for cancer control. 

Another important aspect of the research effort to find new 
methods of cancer diagnosis centers around the peripheral blood studies 
that I described to the Committee last year. Since then, this important 
work has progressed fruitfully; and I can now repoirt that a group of our 
scientists recently described a technique for preparing human whole 
blood so that it can be examined cytologically for the presence of 
malignant cells. 

In each of several experiments to test the procedure, tumor 
cells from a variety of soiorces were added to samples of human whole 



- n - 

ivlood. In each experiment, the number of t\jmor cells detected was 
virbxially identical to the number of cells originally added to the 
whole blood. In no case was the margin of error greater than ten 
percent. Furthermore, the recovered tumor ce3J.s were intact, which 
means that it was possible to determine the type of malignant growth 
from which they had originated. 

The scientists concluded from these studies that their method 
seems to fulfill all the requirements of an ideal procedure for 
processing samples of "blood containing tumor cells for microscopi 
examination. We consider this to be an achievement of the first 
importance. Further research, now in progress, is aimed at ascertaining 
the significance of circulating tumor cells in individual patients 
affected with various types of cancer. This work will require at 
least five years to complete. 

The progress achieved within the past several years seei.ii to 
substantiate the belief that we are on the threshold of some fiindamentai 
improvements in cancer diagnosis. Certainly the development of the 
cytologic technique is of tremendous importance. Perhaps it will be 
possible to develop other ways of finding cancer early, when it is most 
responsive to treatment, and in this way sharply reduce the loss of life 
from malignant disease. 

The cytologic technique for the detection of cancer of the 
uterine cervix, which has been intensively studied by the National 



- 12 - 
Cancer Institute for more than ten years, is now an esta'blished, 
widely-used cancer control measure. Last December 15th, the Bureau 
of State Services of the Public Health Service established a unit, 
with the technical help from the National Cancer Institute, for the 
application of uterine cytology to the control of this form of cancer 
in the population. However, the National Cancer Institute still retains 
a vigorous cytology research program, which is aimed at gathering much- 
needed information on the natural history of uterine cervical cancer, 
uti3_izing cytology in the study of malignant cells in circulating blood;, 
and at perfecting methods of applying cytology to the detection of cancer 
of other body sites, such as the lung, genitourinary system, and colon. 

Permit me to describe some of the basic ideas underlying the plan^^ 
for the operation of the new Cancer Control Program of the B\ireau of 
State Services. 

It is incumbent upon us to see that no opportunity is overlooked 
to ensure that the maximum benefits from past and future research accom- 
plishments are realized without avoidable delay. To accomplish this 
objective, we consult with interested groups concerned with stimulating 
local practicing physicians, who are the focal point of all community 
cancer control efforts, to put to use the latest . information and tech- 
niques. Since a local, as well as a national, cancer control program 
can be successfully carried out only as a cooperative venture among 
private physicians, medical groups, voluntary agencies, hospital and 



- 13 - 
j-aboratory personnel and public health officials, these resoiarces must 
"be mobilized in a cooperative, integrated effort. Support is required 
to organize and assist this combined leadership in developing their 
programs, particularly in areas that promise important immediate results 
such as cervical cancer casefinding and i)rofessional education. 

The national network of public health services can make a major 
and unique contribution to this effort. Its officials work in almost 
all the nation's communities and closely coordinate their activities 
with the services of private physicians and interested professional 
and voluntary agencies. As a result, they can help local doctors and 
other interested groups in adapting new practices to local conditions 
and In organizing educational programs. The Cancer Control grant-in-aid 
program — $2,250,000 in the budget request — has played a major role 
in initiating the work of State and local health agencies in cancer 
control. 

It has been estimated that if all current knowledge were fully 
applied, the five-year suiryival rate for all cancers covild be increased 
from the present rate of 32 percent to over 50 percent. This optimism 
arises, in part, from the following facts: (l) half of all cancers 
grow in parts of the body that are subject to direct examination, (2) 
with early detection, more cancers can be successfully treated and cured 
or arrested, and (3) more effective techniques for the early detection 
of certain common cancers are now available and still others are being 
developed . 



One of the most important dividends we have thus far realized 
from our research investment is the discovery that uterine cancer in 
women can he detected by a simple cybological test before definitive 
symptoms appear and when it is almost always curable. Since this ccuse 
of cancer death -- currently killing about l6,000 women annually — can 
now be practically eliminated, first priority must be given to expanding 
programs in this field. There are today an estimated 6o,000 women in 
the United States with undiscovered asymptomatic cases of invasive 
cervical cancer — if these cases are discovered early and treated 
adeqiaately, almost all these women can be saved; however, the chancea 
of successful ciire fall rapidly as diagnosis and treatment are delayed. 

It is proposed to expand our efforts to foster a more widespread 
application of the cell examination test for cervical cancer in local 
communities throughout the nation. An expanded Cancer Control Program 
staff will work with private physicians and the personnel of State and 
local official and voluntary agencies to help further the widest 
possible use of this examination in screening apparently healthy women 
and to help ensure that all suspicious cases promptly receive required 
care. A number of demonstrations of cooperative systems of casefinding, 
diagnosis and treatment adapted to a variety of local conditions and 
resources will be sponsored and assistance provided to train additional 
personnel, particularly cytotechnicians . Educational services will also 
be focused on showing women the value of periodic examinations so that 
high rates of voluntary participation are achieved. 



- 13 - 
In summary, the increaBlng activities of the Cancer Control 
Program in cervical cancer and other activities will complement our 
other activities by encouraging and assisting the prompt and widetpread 
use of research findings in local service programs. To ensure the 
success of these efforts, activities will be based on full and free 
consultation and cooperation with medical groups and others allied in 
this work. Since the goal of all our labors is to prevent cancer 
illness and death whereever possible, these efforts to ensure the widest 
possible application of available knowledge are an essential aspect of 
our total program. 

THE CHEMOTHERAPY PROGRAM 
The national voluntary program of cancer chemotherapy research 
is now in full operation, with each of its phases functioning at a high 
level of efficiency and effectiveness. You will recall that l-nt vf^nr 
I indicated some imbalances in the program that we felt could be 
corrected within a year. This has now been accomplished, I am happy 
to say, and the chemotherapy activity is now becoming a mature sef^ment 
of the National Cancer Institute program. 

During the year, the clinical trials operation was augmented in 
scope, permitting the careful evaluation of a substantial number of 
anticancer drugs. At present, between 150 and 200 hospital services, 
organized into I8 cooperative clinical groups, are participating in the 
program. More than 70 drugs are being studied against a variety of 



- l6 - 

malignancies; the leukemias, cancer of the breast, prostate, lung, 
rectum, colon, ovary, skin, bone, and other sites. Drugs are being 
tested alone, in comparison with other agents, and as adjuncts to other 
forms of therapy, particiilarly surgery. 

Many of the- drugs now under investigation have been used for 
some time in the treatment of cancer and are well known to the medical 
profession. These are used as references in the evaluation of newer 
drugs. Some of the agents being evaluated clinically have been specially 
designed by scientists in an attempt to develop new and more effective 
anticancer drugs. In most cases, these compounds are still in a pre- 
liminary stage of clinical evaluation involving a limited number of 
patients. Those found s^fe and effective are being placed in full-scale 
clinical trial. 

The information gained through these extensive clinical trials, 
indeed in the entire chemotherapy research program, is valuable beyond 
estimation. Of course, the program could, and hopefully will, lead to 
the development of one or more drugs with which to cure human cancer. 
This undertaking will also unquestionably produce a wealth of scientific 
knovrledge that could not be gained otherwise in so short a time. By 
the establishment of this program, directed as it is at the solution 
of a single health problem, we have created a research mechanism that 
could furnish principles and techniques applicable to the development 
of drug research programs for other disease categories. In a larger 



" 17 - 

sense, though, the intensive search for anticancer drugs will 'benefit 
science generally, "because it will foster the acquisition of nev 
knowledge in many of the "biological and some of the physical sciences 
at a markedly accelerated rate* 

I reported to the Committee last year that the pharmaceutical, 
chemical, and allied industries had begun to take a most active and 
important part in the chemotherapy program. This trend has continued^ 
and I am pleased to report that many of the nation's leading industrial 
concerns are now working under contracts with the Cancer Chemotherapy 
National Service Center. These firms are supplying valuable materiale 
for anticancer screening, attempting to develop improved screening 
techniques, conducting "in-plant" screening programs, and manufacturing 
drugs in large quantities for clinical trials. 

On last July 31st, the Department of Health, Education., and 
Welfare adopted a revised patent policy affecting contracts for chemo- 
therapy research. The policy was formulated in collaboration with 
industry representatives in an effort to encourage greater industrial 
participation in the dinig development phase of the program. The chief 
difference between this and earlier policy statements lies in the 
"march-in" provision, which protects the public interest by assuring 
adequate production of any effective anticancer drug developed through 
research done under contract to the Chemotherapy Service Center. Any 
contractor who develops a useful drug must supply adequate quantities 



- 16 - 
of the material at a reasonable price. Should he fail, the Surgeon 
General of the Public Health Service could assume the right to license 
additional manufacturers or order the primary contractor to do so. 

I am very optimistic about the whole chemotherapy program, as 
this Committee knows. I believe that we are on the right path and that 
we can expect some really Important results to stem from this miderfeaking. 

A more detailed report on the chemotherapy program is being 
submitted separately for the record. 

OTHER RESEARCH ACTIVITIES 
Causation 

A group of scientists working under a grant from the National 
Cancer Institute have reported on laboratory studies undertaken to 
provide additional information on the possible relationship between 
environmental factors and lung cancer. The studies were designed to 
administer suspected cancer -producing substances directly into the 
lungs of animals of a species that does not ordinarily develop lung 
cancer or pulmonary infections. 

In the technique that was developed by these scientists, a 
carcinogenic hydrocarbon, known as DMBA, and a cigarette tobacco tar 
condensate were administered repeatedly alone or in combination into 
a tube leading directly into the lungs of male and female Syi-ian 
hamsters. This procedure simulated the manner in which carcinogens 
might normally reach the lungs. The entire respiratory tract was 
examined at autopsy for the presence of abnormal gx'owt'h. 



- 19 - 

The Bcientists found that DMBA produced a variety of pathological 
changes ranging from abnormal multiplication of normal cells to frank 
cancer. The dose of DMBA administered appeared to be more important 
than the period of administration. Also, tobacco tar did not produce 
any pathological changes in this study. 

Tnere is a gtowing body of knowledge, including both laboratory 
and statistical studies, suggesting that there exists in tobacco tar 
an agent that is associated vith human limg cancer. Another factor, 
considered to be important in the recent sharp rise of lung cancer, 
is air pollution in urban communities. One air pollutant that appears 
to be incriminated is benzpyrene. A group of National Cancer Institute 
grantees recently reported the results of studies aimed at determining 
the carcinogenic activity of combinations of tobacco tar and benzpyrene. 

The study showed that tobacco tar alone failed to demonstrate 
marked carcinogenic activity. However, benzpyrene plus tobacco tar, 
or benzpyrene plus croton oil produced a significantly greater number 
of benign and malignant tumors than did benzpyrene alone. The investi- 
gators feel that these results constitute circumstantial evidence to 
support the concept that air pollution, together with cigarette smoke 
inhalation, could reasonably explain the higher incidence of lung 
cancer among city dwellers as compared with residents of rural 
communities. 



- 20 - 

Tvro important statistical studies of lung cancer mortality vere 
reported last July to the London meeting of the Seventh International 
Cancer Congress. The Public Health Service, as you know, conducted a 
survey among 200,000 United States veterans over a 2-1/2 year period. 
Of the 7,000 deaths among this group, a significantly higher mortality 
rate was observed among regular tobacco smokers than among nonsmokers, 
and the l\ing cancer rate for cigarette smokers was about 10 times 
greater than that for nonsmokers. 

Lung cancer occurs in men about ^ to 5 times as often as in \?omen. 
A two-year study of the medical and smoking histories of I58 women with 
diagnosed lung cancer conducted by scientists of the National Cancer 
Institute showed that of all the factors studied, the only one that 
correlated with the incidence of lung cancer was cigarette smoking. 
None of the other items investigated — coffee drinking, occupation, 
migration, marital status, pregnancy history— was as significant as 
smoking history in association with lung cancer among these women. 
A comparison of male and female nonsmokers showed a slight excess lung 
cancer rate for males similar to the excess mortality for all causes 
at ages over 35 in the United States. This is evidence that there is 
no factor that makes men especially more susceptible than women to the 
risk of developing cancer of the lung. 



- 21 - 

We know that some occupational groups have a substantially 
increased lung cancer risk. One such group is composed of workers in 
the chromate industry, and scientists of our staff are conducting 
studies designed to identify the agent or factor that causes lung 
cancer among these, workers. 

About a year ago, these investigators reported that dusts of 
crude chromite are deposited in the lungs in a biologically inactive 
state might he acted upon by body chemicals, causing the slow release 
of an active form of chromitmi. More recently, these scientists summa'- 
rized the results of experiments in which implants of chromite roasts 
(products of the process of roasting chromite ore) were made in rats 
either in the pleural cavity or muscle tissue of the right thigh. 
All animals surviving an observation period of two years were killed 
and autopsied. The observed occurrence of tumors suggested that 
cbromite ore roast contains chromium in a form that exerts a suf- 
ficiently strong and prolonged effect upon exposed tissues to cause 
cancers. This suggests that lung cancer among cliromium workers may 
be caused in a similar fashion. 

Within the past few months, one of our staff scientists reported 
the results of a comprehensive review of epidemiological data of stomach 
cancer in the United States and abroad. Among the most important 
findings reported are these: stomach cancer rates in the United States 
have declined steadily for both men and women during the past several 



- 22 - 
decades, a trend duplicated in some but not all foreign countries; 
stomach cancer occurs more frequently among persons in the lower 
socio-economic groups hut does not seem to he associated with occupa- 
tion; there is no significant difference in the stomach cancer rates 
for urban and rural residents; higher rates are found in the northern 
United States, paralleling the international trend in stomach cancer 
distribution. 

The scientist reported that none of the available information 
ruled out the possibility that diet may be associated with the produc- 
tion of gastric cancer. Studies of dietary histories coiild resolve 
some apparent inconsistencies in our present information and perhaps 
pinpoint some food item or combination of items that would help to 
explain the epidemiological pattern for stomach cancer. The investi- 
gator also indicated that a study of the role of heredity may provide 
valuable information. 

I am pleased to report that our environmental cancer research in 
Washington County, Maryland is progressing smoothly. This is the study; 
you will recall, in which we are attempting to make a comprehensive 
sur\''ey of the possible role of environmental factors in cancer causation. 
We intend to leave no stone unturned in this search. Such diverse 
factors as type of dwelling, type of soil, background radiation, and 
family history are being analyzed to provide leads on the influence of 
environment on cancer incidence. 



- 23 - 

On November Ik, the Coffman Research Laboratory, Hagerstown, 
Maryland, was dedicated and t\irned over to the National Cancer Institute 
to provide facilities for this project. The Coffman Laboratory is a 
gift to the County of Mr. and Mrs. Andrew K. Coffman, of Eager stown. 
Use of the building by the Cancer Institute was made possible by the 
V7ashington County Public Health Association and the Washington County 
Health Department. I think this kind of local cooperation is extremely 
important for the success of an environmental cancer study, because it 
means that we will receive ample assistance from local medical autbori"- 
ties and, furthermore, from the local population. Without such help, 
no endeavor of this kind could achieve the desired results. I thinli 
this research is off to a very good start and that we can expect some 
very significant findings to result from it. 

CHARACTERISTICS 

Institute scientists have reported some interesting results of 
lengthy investigations of two lines of cells that were derived in 
tissue culture from a single mouse cell. The two cell lines differ 
markedly in their ability to produce tumors when injected into mice. 
The "high" line cells grow into tumors in 97 percent of the mice into 
which they are injected, while the "low" line cells produce tumors in 
only 1 percent of the mice injected. 

Various characteristics of the two cell lines have been studied 
in an effort to find an explanation for this difference. The scientisoj-' 



- 2if - ■ 
found that the lines differ in growth characteristics; the cells of 
the "high" line proliferated more rapidly during the first few days 
after implantation, spread more rapidly into surrounding tissue, and 
induced enlargement and convolution of nearhy blood vessels, which did 
not occur \rith the "low" line cells. 

Investigation of the metabolic properties showed that the high 
line cells utilized apprpximately three times as much glucose as did 
the "low" line cells. Biochemical studies showed still other differ- 
ences in the makeup of the two lines. The scientists concluded that 
the "low" line cells were more nearly like normal cells, while the 
"high" line cells had been substantially altered in tissue culture. 
Thus "high" line cells may respond differently to some growth 
restraining influence in mice as a result of their altered metaboljc 
patterns . 

Institute studies on water-soluble diets have been profitably 
continued. These are chemically defined synthetic diets containing all 
known nutritional requirements to sustain life. Laboratory animals 
receiving these diets mate, bear normal, healthy young, and lactate. 

With respect to human use, the water-soluble diets have been 
found to be edible and should prove of value in the care of patients 
with alimentary problems. The diets are particularly significant in 
that they open the possibility for a completely synthetic diet to be 
administered to patients who cannot eat. In their present form, the 



- 25 - 

diets offer many possible advantages by virtue of their small bulk, 
such as economy of storaii;e for civilian defense, arctic habitation, 
and space travel. Animals fed the diets pass very small amounts of 
excreta, indicating a further advantage for human use under special 
conditions . 

It has been suggested that removal of a primary tumor hastens 
the spread of the disease and the growth of secondary lesions. In an 
experimental approach to this problem, staff scientists carried out a 
number of studies on mice three weeks after they had been injected with 
ttmior cells in a hind leg. Subsequently, the mice were sacrificed and 
their lungs examined for the presence of metastatic cancer. 

The first study showed that in mice on which amputation of a 
normal leg or no amputation was performed, the frequency and number of 
metastases were not significantly different. However, removal of the 
leg bearing the implanted tumor resulted in a significantly increased 
frequency, niimber, and size of pulmonary metastases. Removal of the 
primary tumor at the end of three weeks reculted in larger metastases 
than those observed in mice in which the primary tumor was present for 
six weeks. The investigators concluded from this study that a primary 
tumor exerts an inhibitory Influence on distant metastases and that 
removal of the tumor acts as a stimulus on the metastatic process. 

A second study showed that neither cortisone nor anesthesia 
administration nor operative procedure had any effect on the number of 
metastatic lesions in the lungs. 



- 26 - 

A third study indicated that the anticancer drug TSPA, was 
effective in reducing the number of pulmonary metastases when ad- 
ministered several hours after removal of the primary leg tumor. 
Metastases were completely prevented in some mice. These investi- 
gators feel that their studies in animals closely approximate the 
clinical situation occurring following surgical removal of a primary 
ti;imor . 

TREATMENT 

The most active area in research on the treatment of cancer 
continues to he chemotherapy. I would like to summarize briefly a 
number of developments that are illustrative of progress in the field. 

A group of Institute grantees has reported promising results 
in animal stiidies of the newly-synthesized anticancer drug azauridine. 
This agent is chemically related to 6-a2auracil, which has been used 
with encouraging results in the treatment of human cancer, Azauridine 
was found to be significantly more effective than 6-azauracil in 
inhibiting the growth of three mouse tumors. 

In another grant -supported project, four compounds, administered 
silmultaneously, produced marked regression of breast cancers in mice, 
V/hen these drugs were administered singly, or in any combination of 
three, the best result achieved was a stoppage of timior growth. These 
res\ilts support the principal of simultaneously attacking t^umor cells 
by a nxjmber of pathways as one means of improving the effectiveness of 
known anticancer agents. 



- 27 - 

Scientists of the National Cancer Institute have developed an 
assay procedure for measuring precisely the effectiveness of anticancer 
drugs. In general, the procedure involves administering drugs to mice 
that have far advanced, systemic leukemia. Only drugs possessing a 
high degree of anticancer activity can significantly prolong the life 
of such mice; hence this assay is of particular value in the coraparlBon 
of the therapeutic value of anticancer drugs. These scientiBto found 
that a new drug, dichloromethotrexate, is strikingly more effective 
than its parent compound, methotrexate, in increasing the survival tirae 
of leukemic mice. Heretofore methotrexate had been the most effective! 
drug kno-vm. This new drug has "been placed in preliminary clinical 
trial under the program of the Cancer Chemotherapy National Service 
Center. 

For the past several years. Institute scientists have reported 
highly encouraging results of the chemotherapy of a rare form of 
uterine cancer known ©s cSacariocarcinoma. The patients have been 
treated with the dru^ nnetiStotxexate, administered according to a 
specially devised, intensive regimen. Within the past fe\j months, 
these scientists published a progress report on their work, which I 
should like to stimraarize briefly. During the past two and one-half 
years, 27 women have been treated. All but five of them were gravely 
ill on admission to the Clinical Center. Most of them showed lung 
metastases, and a few presented evidence of central nervous system 
involvement . 



. 28 - 

Complete remissions with no evidence of recurrence for periods 
of 8 to 29 months? were olDserved in 5 patients. Eleven patients showed 
remission with persistent manifestation of disease, and the remaining 
11 patients died either after initial remission or during initial 
therapy without response. The investigators conclude that chorio- 
carcinoma and certain related tumors are initially highly sensitive 
to the drug methotrexate and that substantial clinical improvement 
can be obtained. 

Similar studies are being carried out by National Cancer 
Institute grantees, who have reported equally encoiiraging resiilts 
in this important area of clinical chemotherapy research. 

As you know, the drug methotrexate is widely used in the treat- 
ment of leukemia and is one of the most effective drugs against this 
form of cancer. Grantees of the National Cancer Institute have reported 
the results of a clinical study in which this drug was employed in the 
treatment of neurological manifestations of leukemia, which heretofore 
have not responded well to drug treatment. Methotrexate was injected 
into the cerebrospinal fluid of five leukemic children without serious 
toxic effect. All five patients experienced clinical improvement of 
neurological symptoms. Two of the patients who had become paralyzed 
due to spread of the disease to the central nervous system regained 
the use of limbs and extremities. Another patient, blind as a result 
of neurological involvement, regained her sight and was able to play 



- 29 - 

actively. Two patients who were considered refactory to methotrexate 
showed favorable neurological response after intraspinal drug therapy. 
This study indicates that the control of neurological manifestations of 
leukemia by intraspinal injection of chemotherapeutic agents may become 
a valuable procedure in providing total care of the leukemia patient. 

About 18 months ago Institute grantees described the development 
of a new anticancer drug, 5-fluorouracil, which has now been evaluated 
in preliminary clincal studies. The drug was administered in adequate 
therapeutic dosage to 35 patients afflicted with a variety of malignant 
tumors. Nine of the patients showed objective regression of solid 
tumors, and the majority of patients treated reported subjective im- 
provement and decrease of pain to such an extent that analgesics were 
no longer required. Among the types of cancer that responded to the 
drug were tumors of the breast, liver, rectum, and several other sites. 
The toxic effects of 5-fluorouracil are of relatively short duration 
once the drug is withdrawn. Thus far, in patients with solid timaors 
that have responded to the agent, no development of drug resistance has 
been observed. Some derivati'/es of 5-fluorouracil are being developed 
and studied in preliminary anticancer tests. One of these, 5-fluoro- 
deoxyuridine, is now in early-stage clinical trial. 

CONCLUSION 

The program of the National Cancer Institute is continuing to 
add to the store of knowledge of ma-llgnanb dlBea&e. Much new and 



- 30 - 
valuable information has been gained dxiring the past year, information 
that I believe brings us closer to the achievement of our goal *-- the 
elimination of cancer as a major cause of suffering and death. 

Virus research is being intensified and is starting to produce 
results that may provide a means of preventing human cancer. Our work 
in cytology and other approaches to the detection of cancer seem to 
offer the promise that eventually nearly all cases of cancer will be 
foiind and brought to treatment before symptoms appear, when the 
opport-unity for complete cure is highest. Our expanded control 
activities are designed to hasten the day when this objective will be 
achieved. Finally, chemotherapy research, by far the largest single 
aspect of the National Cancer Institute program, remains a bright hope 
for the treatment of malignant disease. In each of these areas, and 
in fundamental research at the cellular level, our scientists and 
grantees are making important contributions. I am confident that their 
efforts v/ill ultimately put an end to the problem of cancer. 

I appreciate the attention the Committee has given to this 
discussion. I shall be glad now to answer any questions or assist in 
further discussions of our activities. 



EFFECT OF HOUSE ACTION 

The House Conmittee on Appropriations in acting on the eprji-o- 
priations for the Department of Health, Education^, and Uelfare for 
i960 increased the President's budget by {i"8,OSO,000 for the National 
Cancer Institute. As the Secretary indicated, this increase is 
contrary to the fiscal policy of the President. Hoiiever, at the 
request of the Senate Appropriations Committee the following state- 
ment is suhmitted in explanation of how this increase, if enacted, 
would he applied. 

Activity No. l(a). — Research projects 

The full Binotmt requested of $29,209,000 iras allowed by the House and 
an increase of $4,500,000 was provided for addi.tional research projects. 
The total of $33,709,000 is an increase of $5,077,000 over the 1959 
appropriation. This increase vrill be used to support research in 
virology, chemotherapy, imnunology, host tumor relationships, genetics^ 
tissue synthesis and carcinogenesis. 

Activity No. 1(b). -"Research fellowships 

Th"^. full amount requested of $l,ij-27,000 v;aB allowed by the House and 
exi increase of $285,000 was provided for additional research fellow- 
ships to support carefully selected scientists devoting full time to 
research training in fields pertinent to cancer research. 

Activity No, 1(c).— Training 

The full amoiint requested of $6,050,000 was allowed by the Ho\.ise and 
an increase of $1,155,000 was provided for this activity. Of the Eouse 
increase, $2^0,000 will be used for training stipends to support 
additional graduate physicians who desire specialized training in the 
diagnosis and treatment of cancer. The remaining $915,000 will per- 
mit addj.tional grants to universities and medical schools for 
training programs designed to increase the supply of manpov/er in 
disciplines needed for cancer research. 

Activity No. l(e).-- Demonstration projects 

The full amount requested of $1,500,000 was allowed by the House. 
This is a new program in i960 for support of special project grants, 
which will permit the Public Health Service to better carry out its 
assigned role of assisting local agencies In conjLunities througho\it 
the nation, to develop progrejns against cervical caxicer, lung cancer 
and in other areas where important prevention and control oppor- 
tunities nov; exist and may develop. 



Activity iJo. 2(a).— Heoearch 

The roll ai;o\int requested of Oll>^0^'-,000 iiiid 675 positions uas 
allov;Gd by the House, and an increace of ;,'^27,COO kind 20 poGitions 
vrac provided for thio activity. The total of ('11,331,000 ie an 
incrcQGe of :;'l, 173,000 over the 1959 appropriation. Of the total 
progran,$891,000 is for the Institute.'c proportionate s?mre of 
Gervicec furnished centrally. The reinainins 0287,000 will pernit 
expansion of Virya Qtudldo", tuc-c^- ceils 'in circulating blood et,iidies 

and cl-iG^CBl insGtnt-dh Qcti^li^^. 

Activity No. 2(b).— Bevievx and approval of grantc 

The t^ili ai?.ount requected of OcJ^tO,OOU and 37 pooitionD v/as allowed 
oy the House, and an increase of 0^1,000 and 10 positions uas 
provided for this activity. The total of 0921,000 is an increase 
of vl24,0C'O over the 1959 appropriation. Of the total increase, 
069,000 is for the Institute's proportionate share of services 
flemished centrally. The rewQining $55,000 and 10 positions ulll 
pen.dt adequate review and approval of the additional Grants to 
be supported. 

Activity IIo. 2(c).— Professional and technical assistance 

The full anount requested of 05,532,000 and ^^79 positions was 
allowed by the House, and an increase of 013^,000 mqd provided 
for this activity. The total of $5,666,000 is an increase of 
'.a, 162,000 over the 1959 appropriation. Of the total procran 
increase, O^37?000 and k2 positions v;ill permit the expansion of 
the cancer control prograr: to foster the ^ore rapid and wide- 
spread application of the available techniques for early 
detection of cancer. The remaining 0725,000 \riLll permit eicpansion 
of the diagnostic developtient program. 

Activity Wo. 2(e).— Administration 

The full aruount requested of $364,000 and 30 positions was 
allowed by the House and an increase of 08>OOO was provided for 
this activity. 'iTie total of $372,000 is an increase of $l6,000 
over the 1959 appropriation. This increase is for the Institute's 
proportionate share of services furnished centrally. 

For overall budgetary considerations, the Departiient has recou- 
:aended that the increase over the President's budget be ellninated 
by the Senate. 



SLMVLARY OF OPENING STATEMENT 

Director, National Institute of Mental Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 
for 
"Mental Health Activities" 



Mr. Chairman and Members of the Committee: 

During 1959 every program of the Institute expanded, and in some 
areas new programs were developed. 

In the research grants program there was a substantial increase 
in the number of studies on problems of schizophrenia, alcoholism, 
mental retardation and psychopharmacology. Support of projects in 
psychopharmacology has increased from about $2,000,000 to approximately 
$4,000,000. A new energizer developed during the past year appears to 
be a promising specific treatment for mental depression and studies are 
being made which may lead to its use in this type of mental illness. 
A large number of projects were concerned with various phases of the 
problems presented by schizophrenia. Twenty-seven studies were devoted 
to evaluating the use of drug therapy in this disease. Many other 
projects dealt with basic physiological, psychological and sociological 
aspects of schizophrenia. Mental Health Project Grants (Title V, P.L. 911) 
number seventy-one and show great promise in developing new concepts in 
the care of the mentally ill as well as encouraging the utilization of 
existing knowledge. 



^ - 2 - 

Shortages of personnel in the mental health disciplines continue. 
Grant support for training of clinical personnel continues and programs 
providing grant support for research training are under way. In the 
research fellowships program, which was markedly expanded, a substantial 
share of the increased funds have been awarded for work in the field of 
physiology. Twenty-three new grants were awarded for research training 
on a graduate level in psychology. A new program providing psychiatric 
training for general practitioners provides for residency training in 
psychiatry and postgraduate courses for the practicing physician who 
intends to continue his general practice. 

The opening of the Institute's Clinical Neurophannacology 
Research Center in cooperation with Saint Elizaheths Hospital highlights 
expansion of the Institute's own research program. Broad clinical 
studies of the action and mode of action of tranquilizing drugs in a 
mental hospital setting and studies in the "basic sciences are expected 
to provide scientific data and insight into problems of mental illness 
not now available. Among the important advances made during the year 
in the Institute's laboratories at Bethesda was the discovery of how the 
body uses and disposes of adrenaline and noradrenaline, hormones which 
are related to a V7ide variety of emotional responses and which hold part 
of the key to the enigma of how biochemistry regulates hxoman behavior. 

Commiinity mental health activities have continued to expand. The 
trend has been towards greater interagency cooperation. Technical and 



- 3 - 
consultative services of the National Institute of Mental Health have 
been increasingly in demand. Illustrative of one type of such assistance 
is the completion of seventeen Technical Assistance Projects on such 
subjects as alcoholism as a mental health problem in business and 
industry, inpatient psychiatric units for children, treatment of 
adolescents, and the role of the community center in promoting mental 
health. These projects serve to strengthen community mental health 
programs by bringing to people working on State problems expert knowledge 
on specific subjects. 

In the field of alcoholism, current projects range from the study 
of basic metabolic factors in alcoholism to attempts to improve treatment 
methods for alcoholics in outpatient clinics. At the Institute's 
Addiction Research Center in addition to studies of alcohol addiction 
per se , work is being done on personality tests, patients' habits and 
attitudes of alcoholics as compared to drug addicts. Technical and 
consultative assistance provided to the States in the field of alcoholism 
has been accelerated. Two national level conferences were held during 
the year to review present knowledge and programs in the field in 
conjunction with future planning. 

The Institute has continued to work closely with the States in 
collecting, analysing and interpreting statistical data on mental 
hospital populations and outpatient psychiatric clinics. Recent studies 
by NIMH biometricians revealed striking differences between State mental 



- k - 

hospital systems in the likelihood of patients being released from or 
remaining in the hospital. These differences appear related to the use 
the conmiunity makes of the hospital, and they raise serious questions 
about the future of the large mental hospital. 

Liaison and consultation with mental health specialists in other 
countries during the past year resulted in interchange of information 
about new developments in psychiatric research and in treatment 
techniques both here and abroad. Many rapid advances are being 
contributed by scientists and mental health specialists throughout the 
world, and medical researchers are beginning to synthesize all of these 
new findings into an integrated international attack on the problems 
of mental illness. 

The request before the Committee for I96O is $52,38^,000 which 
including the comparative transfer, is the same as the 1959 appropriation, 
but $^-1-61^000 greater than the 1959 obligation plan. 



OPENING 3TATS?!ENT 

by 
Director, National Institute of Mental Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"Mental Health Activities, Public Health Service" 



Mr, Chairman and Members of the Committee: 

The budget proposed for Mental Health Activities is $52,384,000 
which T-Tith the comparative transfer is the same as 1959 » but $2,411,000 
greater than the 1959 obligation plan. 

A review of the research conducted and supported by the Institute 
during the past year shows increasing emphasis on studies of the brain 
and its function as an important element in understanding behavior, A 
dramatic example of this trend in mental health research was provided 
hy a recent scientific television show produced on the CBS Conquest 
hoxir. This shoxr depicted investigations linking neurophysiological 
structure and fxinction with total behavior. It is obvious that impor- 
tant advances in the campaign against mental illness will come from 
improvements in our conceptions of how the brain and central nervous 
system operate, and of how these operations correlate ^-dth their observ- 
able manifestations — man's actions, his personality, and his social 
relationships. Scientists doing basic laboratory and clinical research 
have been improving steadily and increasing the number of tools and 
techniques at their disposal, and have accumulated useful knowledge 



- 2 - 
about extremely complex physiological and 'biochemical processes. Be- 
havioral scientists and investigators conducting clinical studies have 
added new methods to their armamentarium and substantially increased 
our understanding of basic psychological mechanisms. Both basic and 
clinical researchers in mental health are now reaching a stage at 
which they can fruitfully combine efforts to comprehend common problems 
and to synthesize and interrelate their respective findings. 

Investigators in Europe and in this country, some of them assisted 
by National Institute of Mental Health grants, are continuing highly 
significant experiments which relate central nervous system mechanisms 
to motivation and drive. They have shown that specific areas of the 
brain can be activated electrically or, in some cases, chemically to 
elicit behavior directed to the satisfaction of specific drives. The 
drives so generated can be used to lead the animal to utilize its intel- 
lectual and physical resources in goal- seeking activities. One of these 
investigators, exploring the separate elements of conflicting drives, 
has developed a framework for what may prove to be a highly effective 
approach to the evaluation of the psychological effects of drugs on 
animals. An Institute investigator is making impressive progress toward 
characterizing the specific brain loci responsible for activities that 
contribute to the individual's survival and his part in survival of the 
species. 

Disorders of thyroid metabolism have long been known to be 
related to various forms of retardation. Institute investigators have 



- 3 - 

made progress this year in eacploring the metabolic pathways that 
destroy and change thyroxine- -the active hormone involved in this 
process. Other Institute scientists have been recording the electrical 
activity of the brain during sleep and the process of awakening, and 
have discovered differences which may account in part for dream activ- 
ity. These studies are basic to our understanding of the physiology 
of sleep as well as of perception, attention, and memory. 

The Institute's opportunities for interdisciplinary research 
have made it possible for us to exploit the new techniques available 
for re-e3q)loring relations between bodily structure and functioning. 
Increasing attention is being given to studies at the borderlines 
between psychology, chemistry^ and physiology in the laboratories of 
the National Institute of Mental Health. An interdisciplinary study 
of human aging, conducted by a team of Institute psychologists, psychi- 
atrists, sociologists, and biological scientists, is now in the data 
analysis stage. One finding of this study discloses a parallel rela- 
tionship between the individual's cerebral metabolism and his ability 
to cope with his environment. The Institute is also beginning studies 
on endocrine function associated with psychological stress. 

The official opening during the past year of the Institute's 
Clinical Neuropharmacology Research Center, in cooperation with 
Saint Elizabeths Hospital, adds to the opportunities for combined 
basic-clinical research. Here psychiatrists, psychologists, pharma- 
cologists, biochemists, physiologists, and other research specialists 



- k - 

will conduct a broad program of studies, including a systematic 
survey of suitable population samples, with special reference to the 
impact of pharmacotherapies on the existing services of a mental 
hospital. This includes research designed to measure changes in 
hospital management and care brought about by the use of the drugs, 
and how such environmental changes in turn affect the symptoms of ill- 
ness in the patient. The Center will also carry on human studies in 
intermediate metabolism in order to establish biochemical correlates 
of reaction patterns, and will examine the effects of drugs on enzymatic 
processes concerned in the synthesis, storage, and release of neurohumoral 
agents within the brain. The Center will conduct hviman psychological 
studies, particularly on the processes of attention, perception, sensory 
discrimination, and learning. An attempt also will be made to establish 
objective measures of those aspects of thought disorder which are 
characteristic of the schizophrenic syndrome and which are measurably 
affected by drugs. 

Increased interdisciplinary research by investigators outside 
the Institute is being supported through the grants program. The 
policy of providing assistance to large program-type research efforts, 
which particularly lend themselves to combined clinical and laboratory 
studies, continues to be implemented. In recognition of the need to 
develop increased numbers of investigators qualified to carry on 
research which cuts across several areas of disciplinary specialization, 
the Institute last year initiated additional programs of support for 



- 5 - 
training in the biological and "behavioral sciences. Support for train- 
ing in mental health disciplines is now available to biological and 
behavioral scientists who wish to bring their research talents to the 
field of mental health. Support is also now available to enable mental 
health professionals to receive training in biological and behavioral 
sciences so that they can bring their rich clinical experience to bear 
on research problems. 

I have emphasized some of the developments in cross-disciplinary 
efforts in mental health because I feel that cooperative basic -clinical 
research holds the most exciting promise for future progress against 
mental illness. The influence of this trend can be seen in virtually 
all the important areas with which the Institute is concerned. 

RESEARCH GRiWTS 

This year saw substantial increases in the number of investiga- 
tions on problems of schizophrenia, alcoholism, mental retardation, and 
psychopharmacology. A heavy share of the research grants program has 
continued during 1959 to support studies concerned with developing 
improved methods of care, treatment, and prevention of mental illness, 
and with such basic problems as the biology and biochemistry of mental 
illness, the role of psychological and social factors in noimal and 
abnormal behavior, child development, the epidemiology of mental ill- 
ness, and such problem areas as juvenile delinquency, aging, and school 
mental health. 



- 6 - 

In the field of alcoholism, program stimulation has resulted 
in the submission and approval of new and promising research grants. 
Current projects range from studies of the hasic metaholic factors in 
alcoholism to attempts to improve treatment methods for alcoholics in 
outpatient clinics. Other studies include the effect of alcoholism on 
a person's physical and mental health, the relation between alcoholism 
and personality, and a cross-cultural investigation of the prevalence 
of alcoholism. 

A substantial amount of research in juvenile delinquency is being 
supported by the Institute, including such studies as the relation 
between community structure and delinquency, intrapersonal factors in 
juvenile delinquency, family factors in delinquency, the rehabilitation 
process in reformed offenders, and a study of the development of self- 
control in children. Several studies of the psychological and 
physiological effects of the addictive drugs have imder lined quite 
dramatically the relation of delinquency to addiction and the Importance 
of the transitional period from adolescence to adulthood as the key 
period for effecting long-range changes. Because of the desirability 
of studying these two problems simultaneously, the next step is the 
development of a demonstration project in this joint area. 

Several of the grant- supported research projects in mental retard- 
ation have reported findings. At Bellevue Medical Center in New York 
one grantee has announced the possible development of a synthetic amino 



- 7 - 
acid diet to correct "maple sugar urine disease, " a condition character- 
ize d by early and rapid mental deterioration associated with a marked 
maple sugar odor in the urine. An Institute grant to the Pacific State 
Hospital is supporting a study of the impact of institutionalization 
on the mentally retarded. Preliminary findings indicate that physical 
rehabilitation programs help increase the patients' readiness for 
discharge. Improved patterns of ward management also result in improved 
discharge rates, irrespective of changes in the patients' I.Q. 's. The 
grant to the National Association for Retarded Children for a study of 
the etiology of mental retardation resulted in a major report. Published 
early in 1958 in two separate monographs, it since has been republished 
in book form for wide distribution. In addition, Institute staff have 
taken active steps to develop leadership in professional organizations 
working in the field of mental retardation. 

The National Institute of Mental Health has joined with other 
Institutes in supporting several large interdisciplinary program grants 
in aging. In addition, it independently supports other research on 
aging, such as the effect of aging on the central nervous system, the 
treatment and prevention of senile arteriosclerosis, better methods 
of measuring the health of the aged, psychiatric rehabilitation of 
older persons, the effects of retirement, and a variety of other aspects 
of the aging process. Several groups of researchers are engaged in 
developing psychological tests for use with the aged. 



I , .. .; •■■ 



-..•T" 



- 8 - 

Studies in basic research constitute at least half of the total 
mental health research grant program. The broad spectrrmi of research 
being underwritten in psychophysiology includes such projects as 
endocrinological determinants of behavior, studies of autonomic 
response patterns, and relations between attitude and physiological 
change. At the University of Michigan's Department of Psychology, 
research is being supported on brain functioning. Extending techniques 
of self- stimulation through implanted electrodes in the brains of rats, 
the investigator has helped to extend brain mapping into the area of 
clearly defined motivational functions. This research is typical of 
a number of ciirrent research studies on motivation and reward, which 
ultimately may have wide clinical, social, and educational implications. 

PSYCHOPHARMACOLOGY 

This past year saw a 100 percent increase in Institute supported 
research in psychopharmacology. This has resulted from increased nation- 
wide interest in psychopharmacology research, availability of more funds, 
and active stimulatory efforts by the staff. Equally significant is the 
fact that, in the judgment of the Institute's advisory bodies, clinical 
research in this field is steadily improving in quality. It is apparent 
that an educative process has been taking place as a result of the focus 
on well-designed clinical studies. This change in level of sophistica- 
tion of the research means that all the results can be accepted with 
much more confidence and that the clinical use of the psychiatric 
drugs will be based on much sounder data. 



- 9 - 

Progress was made in the area of new drug development. Several 
new agents are now available in the treatment of depression. These 
include the energizers iproniazid, orphenadrine, and imipramine. The 
latter compound is not a stimulant or a tranquilizer, but may be re- 
lated to some of the psychotomimetic substances which produce transient 
symptoms similar to mental illness. Two potent and structurally quite 
different groups of psychotomimetic drugs were developed in the past 
year. One group produces a much more potent and disturbing "psychotic" 
state than either LSD or mescaline; the other disorganizes thought and 
produces dramatic disturbances of body image. The Institute is now 
supporting two studies which have as their major objective the identi- 
fication of useful new drugs, and a number of other grant applications 
of this nature are awaiting review. 

The research being done in psychopharmacology ranges from clinical 
testing of drugs to synthesis of new compounds. Definitive studies of 
the clinical efficacy of drugs have more than doubled during the past 
year. The Institute is now supporting 2? clinical projects designed 
to evaluate 17 different psychiatric drugs. The trend in the past 
year has been toward greater diversification of drug testing among 
patient groups, increased interest in gauging the efficacy of drugs 
in maintaining patients in the community, and improvement of methods 
for evaluating clinical improvement. 

Because of the large numbers of persons suffering from schizo- 
phrenia, special emphasis has been placed on evaluating the usefulness 



- 10 - 
of psychopharmacologic treatment. Twenty- seven projects on drugs and 
schizophrenia are now being supported; 17 are concerned specifically 
with chronic schizophrenics who have been in the hospital for many 
years, and 10 are studying drug therapy for acute patients with recent 
onset of illness. Most of this research is being done in hospitals. 

Evaluation of the effects of drugs on children is needed. As 
was emphasized at a recent conference on Child Research in Psycho - 
pharmacology sponsored by the Institute, there is virtually no system- 
atic knowledge of drug effects on the behavior of children. The 
increased funds received in 1959 enabled the Institute to support 
three new studies of drug effects in children. These studies, being 
conducted in both hospital and outpatient clinics, include evaluations 
of drug effectiveness in alleviating anxiety and in controlling hyper- 
activity, and investigations of the effects of chlorpromazine on 
learning ability and memory. 

The Institute is organizing cooperative clinical trials to 
test new drugs systematically as soon as they are released by the Food 
and Drug Administration. This program is beginning with a pilot study 
at Saint Elizabeths Hospital, after which two more hospitals will be 
added to the trials. Comparing the data from these three hospitals 
will show whether consistent results are being obtained. If this 
preliminary work shows promise, additional hospitals and clinics will 
then be added, with each group of three hospitals evaluating three 
drugs and a placebo. This program will not only produce information 



'i-L- 



,■■ J 



- 11 - 

about the clinical effectiveness of drugs, "but will also build up a 

core of investigators trained in psychopharmacological research who 

will be able rapidly to evaluate new drugs as they become available. 

A detailed report of the activities of the Institute's Psychopharmacology 

Service Center is being provided in a separate document. 

NATIONAL INSTITUTE OF MENTAL HEALTH 
LABORATORY RESEARCH PROGRAM 

Multidisciplinary basic research on fundamental problems of 
physiology and the relation of physiological function to behavior 
continue to provide the theoretical basis for the Institute's intra- 
mural basic research program. In the field of cellular pharmacology, 
work was concentrated during the past year on studies on biological 
methylation, amino acid metabolism, protein synthesis ; and comparative 
biochemistry. Research in physical chemistry centered on the structure 
and physical chemistry of the nucleic acids, the large molecules found 
in the nucleus and cytoplasm in all cells which are believed to be 
the material responsible for transmitting genetic information from one 
generation to the next. 

Institute researchers in neurophysiology are investigating bio- 
chemical differences in various parts of the brain; using animals 
ranging from mouse to monkey. Since specific chemical poisons 
(antimetabolites) affect different regions according to the local 
dominance of differing metabolic processes, they provide a useful 



_12 _ 

tool for distinguishing and differentiating between functional 'biochem- 
ical systems. This research contributes to basic knowledge of the brain 
mechanisms and has specific implications for studies of alchoholisl^m and 
dr\ag addiction. Institute neurophysiologists also are pursuing research 
on the limbic system, part of the phylogenetically old brain which is 
yielding new concepts related to the basis of emotional experience and 
expression. 

Among advances made during the past year was the identification 
of the enzyme responsible for inactivation of epinephrine and norephin- 
phrine, two neurohumoral agents which play an important part in the func- 
tioning of the nervous system. Such mental subnonnalities as cretinism 
may be ejqolained by recent animal and test-tube experiments which have 
demonstrated the action of thyroid hormone in portein synthesis, pro- 
bably the major mechanism of action of this hormone. This finding 
accounts for the effects of thyroid hormone on the metabolic rate and 
helps to explain many of the clinical features of hyperthyroidism, in- 
cluding the retarded development of the body and brain in cretinism. 

Studies on the neurophysiological mechanisms involved in sensory 
input and perception have revealed part of the complex relationships be- 
bween the reticular formation (located in the brainstem region of the 
old brain) and sensory circuits. The reticular formation participates 
in the physiological events responsible for wakefulness and sleep, 
focus of attention, habituation, and governs the control of sensory 
lijHput. 



- 13 - 

The Institute's laboratory research in the work of psychology 
of the aging process has progressed from nerve conduction and reflex 
timing to comparisons of higher thought processes, with emphasis on 
those variables related to adaptiveness of the individual. Animal 
behavior research has concentrated on (a) comparing the behavior sub- 
sumed by the frontal and temporal lobes in monkey, chimpanzee, and man, 
and (b) analyzing particular aspects of the neural substrates of this 
behavior. Other animal experiments aim at developing principles of 
building physical and social impositions into the environment which 
will lead to cooperative or competitive behavior over which the animal 
has no choice or control. 

The Institute's Addiction Research Center at Lexington, Kentucky, 
continued its national and international role in defining the addictive 
properties of new drugs which it analyzes for theoretical research 
purposes as well as for protection of the public. During the year eight 
new analgesic drugs were tested. Evidence and conclusions relating to 
five of these were submitted to the National Research Council Committee 
on Drug Addiction and Narcotics. In its work on the psychology of 
addiction, the Center has been attempting to develop an experimental 
analogue in rats of "relapse" to the use of narcotic drugs by man. Much 
progress has been made on the construction of an inventory for assessing 
the subjective effects of several different classes of drugs of interest 
to the Center (opiates, hypnotics, psychotomimetics, tranquilizers, 



- Ik .. 

and stimulants). This project has implications for psychopharmacology 
and is directed toward providing a more objective measurement of the 
mental effects induced by drugs. 

A nujnber of the Center's studies are related to alcoholism^ 
including a comparison of the habits and attitudes of alcoholics with 
those of addicts; a comparison of personality test patterns of alcoholics^ 
addict prisoners ; and addicts on opiates; effects of drugs on learning; 
the effects of drugs on sensitivity to various classes of stimuli; and 
the neurophysiology of chronic intoxication with hypnotic and seda- 
tive drugs. 

NATIONAL INSTITUTE OF MENTAL HEALTH CLINICAL 
INVESTIGATIONS PROGRAM 

During the past year, significant developments occurred in the 
Institute's clinical investigations program, including the establish- 
ment of the collaborative research program with Saint Elizabeths Hospital 
(Clinical Neuropharmacology Research Center). In addition;, plans for a 
field study of factors involved in successful adaptive behavior to 
normal like stresses are nearing implementation. These clinical and 
field studies are supported by appropriate laboratories where the data 
gathered by observation, therapHy, and clinical trial can be ampli- 
fied and extended. 

The Institute's work with hostile aggressive children has 
contributed significantly to the understanding of the impact of milieu 
on behavior, of the development of impulse control, and methods of 



- 15 - 
treatment based on psychodynamic principles. Results of this research 
are now being prepared for publication and will be available in the 
near future. 

During the past year, the work in adult psychiatry has approxi- 
mately doubled. New directions have been charted for research, and 
extensive long-range planning has been undertaken. The various projects 
are being carried out by psychiatrists and by research workers in psy- 
chology, sociology, physiology, and other related fields. V/ork is being 
done not only in the hospital, clinic and laboratory, but in field set- 
tings as well. Greater attention is being given to method than has been 
characteristic of psychiatric research, with major focus on basic pro- 
cesses relevant to many important problems of human behavior. Two new 
sections organized during the past year, one on psychosomatic medicine, 
the other on personality development, represent two aspects of a broad 
program of research on stress and adaptation. A major part of the work 
in adult psychiatry carried on by the Institute includes research on 
psychotherapy and a number of studies on schizophrenia. The research 
in schizophrenia conducted by Institute investigators is described in 
a later section. 

During the past year the first substantial steps were taken 
toward implementing the Clinical Neuropharmacology Research Center's 
program in its permanent quarters in the V/illiam A. White Building 
of Saint Elizabeths Hospital. The Center will maintain active and 
sustained collaboration with the other Institute laboratories. 



- 16 - 

Psychologists in the Institute's Clinical Investigations pro- 
gram have been working on the observation and indentification of basic 
processes of behavior development and personality formation in early 
infancy. Research in this area will contribute useful data for the 
purpose of developing more informed and more adequately documented 
theories of development in early childhood, and of the relations between 
these early characteristics and mental health and pathology at subsequent 
ages. 

Plans have been developed for an intensive stu(ty of creativity, 
a field which has many theoretical and practical implications . As 
presently conceived, this research would place primary emphasis on dis- 
covering those personality and environmental conditions most conducive 
to the functioning of creative effort. 

SCHIZOPHREOTA: EXTRAMURAL AND INTRAMURAX PROGRAMS 

Current concepts regard schizophrenia not as a unitary disease 
process, but as a group of diseases not necessarily related to each 
other and involving the interaction of multiple factors- -genetic, socio- 
cultural, psychological, and biological. The Institute's grant program 
has supported an increasingly wide variety of research in all these 
fields, as well as a series of clinical studies of schizophrenia. Much 
of the psychopharmacology grant program is directly related to research 
in schizophrenia. One National Institute of Mental Health grantee has 
recently reported on the use of a new drug, trifluoperazine (Stelazine), 
in the rehabilitation of chronic schizophrenic patients. 



- 17 - 

Other grantees are investigating the uses of social therapy and 
rehabilitation centers in maximizing the effectiveness of drug therapy. 
The results of one study suggest that patients who are moved from an 
inactive atmosphere of chronicity to an environment where active treat- 
ment is given profit more from drugs than do patients who remain in the 
chronic atmosphere. This study also points to the need for half-way houses 
and other forms of post-hospital care. 

Five projects now underway are investigating the problem of main- 
taining schizophrenic patients in the community. Individual treatment 
programs are planned for each patient, some of them receiving drugs as 
needed. Patients attend mental hygiene clinics, receive home visits 
from Public Health nurses, attend day-care centers, or receive other 
hospital rehabilitation procedures. These research projects should 
provide valuable information on the most effective means of preventing 
rehospitalization among patients released from hospitals after drug 
treatment. One study is designed to learn whether schizophrenic 
patients can be treated successfully at home if drug therapy is given 
under proper supervision. If it is shown that these patients can re- 
main at home rather than be committed to a hospital, it may be possible 
to effect great changes in treatment procedures for the mentally ill 
and reduce the tremendous economic burden of maintaining large State 
hospitals. 



- 18 - 

A number of grant -supported biochemical and neurophysiological studies 
related to sctiizophrenia are concerned with the detection of substances^ 
produced by the body's physical and chemical processes, which may be 
causal agents in the development of schizophrenia. Parallel with this 
is an attempt to find biochemical abnormalities which might be correlated 
with psychological abnormalities. 

Institute investigators are pursuing st\idies of the behavorial 
and biochemical correlates of the electroencephalogram in schizophrenia. 
Further work on theories with respect to disturbance in the circulation 
and energetics of the brain in schizophrenia has confirmed earlier 
evidence that there is no abnormality either in circulation or total 
oxygen consumption of the brain in schizophrenia. 

A major area of research in the Institute deals with family relations 
in schizophrenia. Perhaps the single point on which there has been the 
greatest agreement, at least at the level of clinical impression among 
workers in this field, is that there is some sort of gross defect or 
abnormality of a psychosocial nature in the families of schizophrenic 
patients. 

Progress during I958 in work on family studies included; 

(1) enlargement of the number of families of schizophrenics studies; 

(2) beginning of clinical comparison studies with the families of non- 
schizophrenics; and (3) development of new clinical methods, such as 



- 19 - 
family therapy, in which parents, the patient, and siblings are seen 
together and their transactions are observed directly and studied 
diagnostically through a psychotherapeutic approach. 

In addition to the kinds of research projects and investigations 
described above, the Institute is currently supporting, under its Mental 
Health Project Grants program, a large number of experiments, demon- 
strations, and studies designed to develop Improved methods of diagnosis, 
care, treatment, and rehabitation of schizophrenic patients. 

TRAINING 

Although progress has been made in increasing the number of per- 
sons trained in a variety of mental health disciplines, we are still . 
faced with serious shortage areas. Since its inception, the Institute's 
training program has been dedicated to stimulating an increase in both 
the quality and quantity of professional personnel in the mental health 
diciplines. Until 1958 erophasis was primarily on training clinical 
personnel. This is an area where the needs remain immediate and crit- 
ical. We are therefore continuing to strengthen this program. Begin- 
ning in 1958 the training program entered into a new phase -of its 
development with the expansion of research training and the inauguration 
of two new programs. 
Research training 

The research fellowship program was markedly expanded in the 
current fiscal year. In line with Congressional recommendations, a 



- 20 - 
substantial share of the increased funds has been awarded for research 
fellowships in the field of physiology. 

Currently available support for research training includes: 
grants to four medical schools for the development of interdisciplinary 
training, particularly the research aspects of training for biologic and 
social scientists in the field of mental illness so that there will be a 
broader approach to the solution of the problems of mental health and 
mental illness; medical student stipends for extracurricular clinical 
or research activities in psychiatry; research training on a graduate 
level in psychology. In this latter program 23 new grants were awarded 
during 1959 in nine areas of psychology. 
Other new programs 

As early as 19^7 > the Institute recognized the need for sufficient 
psychiatric training to enable physicians to deal more effectively with 
the emotional problems of health and illness. By 1950, grant support in 
the undergraduate training program was provided to expand psychiatric 
curriculum in nearly half of the medical schools. At present all medical 
schools provide this training. Since no provision was made for the 
physician who graduated prior to 1950, a few grants were awarded during 
the last 10 years for postgraduate psychiatric institutes and workshops 
for groups of general practitioners and other physicians in practice. 
Those pilot efforts have been most successful. 



- 21 - 

Public interest in psychiatric training for general practitioners 
and Congressional support have made it possible for us to move forward 
in this area. The present program provides two types of training for 
the practicing physician - the residency training program under which 
grant support may be provided which enables the practicing physician 
to leave his practice and take training which will mal<:e him a full- 
fledged psychiatrist; the other is for postgraduate courses for the 
practicing physician who intends to continue his practice but who wishes 
to have a better understanding of the psychological factors in health 
and illness. 

Under the program, support is offered medical schools, hospitals, 
clinics, and national and local medical and psychiatric societies to 
develop and conduct postgraduate courses, institutes and seX^mars. The 
response to this program to date is concrete evidence that this type of 
training is fulfilling a hitherto unmet need. Four grants (two resi- 
dency, two postgraduate) have been awarded. Thirteen additional appli- 
cations (10 residency, three postgraduate) have been approved by the 
National Advisory Mental Health Council and funds will be awarded 
shortly. 

COMMUNITY SERVICES PROGRAM 
State activities 

It takes many strands to weave a pattern but the pattern in State 
community mental health programs is emerging perhaps faster than any of 



^ 22 - 

us would have dared to dream ten years ago. In State mental health 
programs there has been a trend toward more interagency collaboration. 
One finds increasing participation of community mental health and 
hospital programs in the training programs of professional schools. 
Federal, State and local funds budgeted in I958 by State mental health 
authorities increased sharply for training of community mental health 
people , 

The Technical Assistance Projects program has been an exceedingly 
fruitful avenue for strengthening community mental health programs, 
coordinating mental health activities in a State and bringing to people 
working on State problems expert knowledge on specific subjects. At 
the invitation of the State Mental Health Authority the Institute helps 
plan and supports workshops or conferences on a particular subject of 
concern to the State. Top experts in the field are invited to attend 
and join with the State personnel in a concentrated study of specific 
problems. Last year I7 such projects were completed. Subjects ranged 
from mental retardation to alcl^oholism as a mental health problem in 
industry. The impact of these Technical Assistance Projects is not 
limited to the originating State since reports of the project are 
published and distributed widely to people in other States. 
Regional activities 

States are cooperating to attack problems of mental illness and 
to promote menteJ. health in a number of ways. We have discussed, in 
other years, the importance of the work of the Southern Regional 



- 23 - 

Education Board, the North East State Governments Conference and the 
VJestem Interstate Commission for Higher Education. This last year as 
a result of the 11-State survey of mental health needs conducted by 
Western Interstate Commission on Higher Education, a Western Council 
for Mental Health Training and Research was established. This organi- 
zation has a ^-year grant from the Institute. Their goals include the 
development of programs in the Western States in mental health train- 
ing and research which cross not only State lines but institutional and 
professional lines as well. Some very practical approaches include the 
development of psychiatric residency programs between universities and 
State hospitals on an interstate basis, specific research and training 
programs which would include summer placement programs for high school 
students, and summer training programs for graduate students. 

The year 1958 witnessed the growth of cooperation through Inter- 
state Compacts. Two States, Kentucky and Louisiana, passed legislation 
ratifying the Interstate Compact on Mental Healih . This brings the 
total to 12 States now participating in this inter-State agreement. 
Under this program State residency requirements may be waived if to do 
so is for the best interests of the sick person. 

Developing mental health services in r\iral areas continues to 
be a major problem. Most mental health services are concentrated in 
cities, especially in metropolitan areas which have professional train- 
ing centers. The most recent data available indicate that only 9 percent 



-^ - 

of professional man-hours of all outpatient psychiatric clinics were 
in rural areas which contained ^1 percent of the population of the 
nation. Several States are experimenting with regional or miolti- county- 
administrative units for providing mental health services. 

In 1939^ only k3 general hospitals in the United States accepted 
psychiatric patients; in 1959, almost 1,000 general hospitals accepted 
these patients. The availability of coverage for mental illness in 
Blue Cross and other health insurance plans has been an important factor 
in this development in many States. Despite this encouraging progress, 
however, the majority of general hospitals still do not provide care for 
psychiatric patients. 
Alcoholism 

Last year, as a result of the stimulus of this Committee's 
action and the appropriation of fimds for work in the field of al- 
coholism, the Institute took steps to expand and strengthen its work 
with the States. To accelerate joint efforts of key people on this 
problem in different parts of the country, two national -level confer- 
ences were held. In January, staff members of the National Institute 
of Mental Health and Public Health Service Bureau of State Services 
met with the Executive Committee of the North American Association of 
Alcoholism Programs. In April, in conjunction with the Bureau of State 
Services, an ad hoc planning committee met with representatives of a 



-25 - 

variety of ofYicial and voluntary agencies with an active interest in 
alcoholism. Present knowledge and programs in the field were reviewed 
in conjunction with future planning. 

The Institute has increased its consultative and technical as- 
sistance services to States and communities with respect to alcoholism 
programs. Consultation was provided on such problems as developing 
more effective treatment and rehabilitation measures in hospitals and 
clinics, alcoholism in industry, alcoholism among the Indians, and 
alcoholism in relation to such chronic diseases as tuberculosis. 

CARE OF THE MENTALLY ILL 

We are in a period of changing concepts with regard to treatment 
of the mentally ill. Traditional ideas of treatment are being chal- 
lenged. There is a growing recognition of the concept that long periods 
of hospitalization are not necessary the best treatment for every 
person who is mentally ill. More and more in Europe and in this country 
the role of the mental ^hospital is being studied in relation to other 
community facilities for the treatment and rehabilitation of the mentally 
ill. 

Mapperly Hospital, Nottingham, England, has developed in that 
community a mental health service which provides for use of the re- 
sources of the home, domicilary services, and community activities in 
the treatment and rehabilitation of the mentally ill. Outpatient ser- 
vices with short-teDHu admission to hospitals, as required for treatment 



-26> - 

or rehabilitation are part of this program. With the development of 
hospital- community cooperation, Mapperly is also an open hospital -- 
there are no locked wards. 

This program, as well as many others, raised interesting ques- 
tions ahout hospital management and the best ways to reduce disability 
from mental illness, which are reflected in a variety of new approaches 
being explored in this country. Establishment of day and night hospi- 
tals, 'open hospitals", emergency care and outpatient treatment ser- 
vices, as well as follow-up and after-care programs, are in operation 
in many areas in the United States . 

Many of the Mental Health Project grants being supported by the 
Institute under the provisions of Title V of the Health Amendments Act 
(P.L. 911) are designed to explore improved methods of care, treatment, 
and rehabilitation of the mentally ill. One State hospital, for example, 
has established an emergency psychiatric team who visit the patient in 
his home and provide intensive emergency treatment there. The study 
will eventually determine the effectiveness of this type of treatment 
as compared with hospitalization. This is somewhat similar to the 
program initiated in Amsterdam, Holland, a number of years ago by 
Dr. Querido. He found it an effective method. Among the 71 Mental 
Health Project grants presently being supported are experiments and 
demonstrations which will provide new knowledge on effective methods 
of care, treatment, and rehabilitation of the mentally ill. In addi- 
tion this program stimulates the use of knowledge already available 
but not widely used. 



-27 - 

BIOMETRICS 

As more new therapeutic programs (drugs, use of day and night 
hospitals, half-way houses and open hospitals) and treatment facilities 
are introduced into hospital and community programs, the task of obtain- 
ing data on people under treatment "becomes increasingly difficult to 
interpret. Yet it is imperative to have data which tells us what is 
happening to the people we are treating. Eleven States in the Model 
Reporting area have con^leted cohort studies which illustrate these 
points. These studies determine prohabilities of release, death and 
retention in the hospital; groups of first admissions matched as to 
age, sex, and diagnosis were followed for the first 12 months of hospi- 
talization. 

These studies demonstrated that there is considerable variation 
among the mental hospital systems of these State and the probability 
of retention, release and death during the first 12 months following 
first admission. A large variety of factors were responsible for the 
differences. These included characteristics of patients admitted, the 
severity of the illness, the characteristics of the communities from 
which the patients were drawn and to which they returned, the presence 
or absence of other facilities for the care and treatment of the mentally 
ill, hospital policies which effect the admission or release of patients, 
staffing patterns of treatment programs, and the philosophy of the 
hospital with respect to the degree of improvement expected in patients 
prior to their return to the community. 



-28 - 

The interaction of factors operating in these hospitals and the 
corcmunities they serve raise the (luestion of how we are going to use 
the mental hospital in the future. For example, public mental hos- 
pitals in areas where there are large psychiatric units in general 
hospitals may receive a higher proportion of patients with poorer 
prognosis than in areas where the mental hospital is the only or 
primary treatment resource. The facts in these studies not only 
demonstrate the significance of this type of information but also 
open new horizons in our concepts of hospital management and the role 
of the mental hospital of the future. What is the optimal size of a 
mental hospital? What is the best relation between acute and continued 
treatment services? How should the mental and emotional problems 
of special groups, such as alcoholics or the aged, best be managed? 
Certainly the mental hospital will be different from that of the past. 
This is as it should be because as man has learned he has moved ahead. 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Heart Institute, 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 
for 
"National Heart Institute" 



Mr. Chairman and Members of the Committee: 

The statement which you have before you is in support of a total 
budget request of $^5^59^^000 which, including the coniparative transfer, 
is the same as the 1959 appropriation, but is $928,000 greater than the 
1959 obligation plan. This figure will permit the solidification of 
past gains in such areas as atherosclerosis, hypertension and training 
to increase the pool of skilled scientific investigators . 

The year 1959 has been productive. Basic and clinical research 
efforts have grown steadily, both in our laboratories at Bethesda and 
in institutions receiving grant support throughout the nation. 

The Heart Institute's program of intramural research continues 
to yield results which add significantly to the existing fund of basic 
biochemical and physiological knowledge. One striking exanrple of the 
application of basic research to immediate therapeutic benefit arose 
within the past year in the treatment of high blood pressure. As a 
result of fundamental biochemical studies begun several years ago, a 
new and promising series of drugs is now under active investigation in 
patients with high blood pressure. If the results of preliminary 
studies are confirmed by more extensive clinical trials, these drugs 
should mark a major advance in the treatment of severe hypertension. 



- 2 - 

Atherosclerosis, the underlying cause of heart attacks and 
strokes J continues as the chief target of our research efforts. 
Here, the most promising area of research appears to lie in studying 
the handling of fatty substances in the "body. To fxirther speed progress 
in this area, the development of a highly sensitive and reliable 
detection device for separating and identifying the components of fat 
mixtiires was successfully undertaken this past year in the Heart 
Institute's laboratories at Bethesda. 

Many promising developments were reported during 1958 from the 
laboratories of institutions and individual investigators supported by 
Heart Institute research grants . Among these advances was the descrip- 
tion of a new surgical procedure to relieve patients s\iffering from 
severe intractable angina pectoris. V/hile only a few such operations 
have been performed, the survival rate has been high and relief has 
varied from partial to complete. New clues continue to be uncovered 
which may one day solve the mystery of hypertension. The relationship 
between psychological stress and hypertension in humans has been further 
elucidated, particiilarly regarding the prognosis of this disease. 

A marked improvement in conventional angiocardiography has been 
achieved. Using this technique in conjimction with induced cardiac 
arrest, it is now possible to demonstrate the position and size of 
certain congenital defects not otherwise detectable. 



- 3 - 

Heart disease continues as the leading cause of death, accounting 
for 5Ufo of all deaths. Mortality in 1957 "was 876,793, an increase over 
the previous year of ahout 33^000 and attrihutahle to the influenza 
epidemic during the fall of 1957* 

The graduate training program has "been expanded and by the end 
of the current year it is anticipated that at least 180 training 
programs will be receiving support. About 100 predoctoral fellowships 
will have been awarded together with 175 postdoctoral fellowships. 

The application of knowledge to reduce rheumatic fever continued 
at a high level during the year with the initiation of six new rheumatic 
fever prevention progrsuns in States and cities throughout the country. 
The number of medical officers assigned to State and local health 
departments to develop new heart disease control activities rose to 22. 

Finally, the National Heart Institute shares in many activities 
of the National Institutes of Health in the international aspects of 
medical research. For example, nearly one hundred scientists from 
foreign coTintries have come to Heart Institute laboratories since the 
inception of the Visiting Scientist and Guest Worker programs . I^ny 
Institute scientists have studied abroad under the Research Fellowships 
program. This Institute has made more than fifty grants for research 
projects in other nations . About thirteen co\intries have been repre- 
sented thus far in the foreign grants area. 



OPENING STATEIVIENT 

Director, National Heart Institute, 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 
for 
"National Heart Institute" 



I^ir. Chairman and Members of the Committee: 

This statement will review for this Committee progress made by 
the National Heart Institute in its mission to achieve workable methods 
for the prevention and treatment of cardiovascular disease. Many 
aspects of the 20 or more disorders of the heart and blood vessels 
continue to baffle the best minds in medical research. Nevertheless we 
are moving ahead in the achievement of both long term and short term 
goals. Altogether this present year has been a fruitful one." . Basic 
and clinical research efforts have grown both in our own laboratories 
in Bethesda and in institutions receiving grant support throughout 
the country. Too, the application of what we now know about heart 
disease has been considerably expanded in many areas, and greater 
emphasis has been placed on community services for the cardiac patient. 
New programs designed to increase the number and quality of trained 
scientific investigators, teachers and skilled physicians were initi- 
ated during the past year. 

Some of the accomplishments and developments of the National 
Heart Institute ' s total program which have occurred during the current 



- 2 - 
year are set forth in the ensiling pages of this statement. 
The i960 request is for $^5*59^^000 which, vlth comparative transfer is 
the same as 1959^ l^ut . t i9Pn,000 greater than the 1959 obligation plan. 

HEART DISEASE TODAY 
Mortality from diseases of the cardiovasciilar system increased 
in 1957 over the previous year — 876,793 deaths in 1957 compared to 
843,410 deaths in 1956. This increase in the total nxmber of deaths 
from cardiovasciilar disease is attributable to the epidemic of influenza 
during the fall of 1957. Preliminary information indicates that the 
cardiovascular death rate for 1958 will approximate the rate for 1957. 
This is because the high level of mortality at the close of 1957 carried 
over, along with the influenza epidemic, into the first three months of 
the year just ended. Percentagewise, however, the death rate ronains 
the same. Fifty- four percent of all deaths in the United States are 
caused by some form of cardiovascular disease. The major component, 
arteriosclerotic heart disease— which includes coronary disease or 
"heart attack"— was responsible for 452,507 deaths. In second place was 
cerebrovascular lesions (circulatory failure in the brain and "strokes") 
with 187,709 deaths. Hypertension was third— 83,500 deaths with or 
without accompanying heart disease— a decrease from a year ago, of almost 
a thousand deaths. A recitation of these figures points up the weighty 
problems presented by diseases of the heart and blood vessels and con- 
tinues to demonstrate the difficulties encountered in solving them. 



- 3 - 
However, recent discoveries and new developments, such as those in drug 
therapy for high blood pressiH*e, and new advances in the field of surgery, 
have added to the existing body of knowledge of the varif onn heart and 
blood vessel diseases. 

DIRECT RESEARCH 

The intramural research program of the National Heart Institute 
is devoted to adding to the fund of basic biochemical and physiological 
knowledge from which fuller understanding of disease must come. It is 
also concerned with the application of such knowledge, to the prevention 
and treatment of diseases of the heart and circulatory system, where 
sufficient development permits. Simultaneously work is carried on at 
the more applied level in the improvement of diagnostic methods, in 
Increasing knowledge of the nature of disease processes and In the 
development of better methods of treatment. These two approaches, from 
the fundamental level and from the clinical level, complement and foster 
each other and continually narrow the gap between them. 
hypertension 

A striking example of the unforeseen application of basic studies 
to Immediate therapeutic benefit has arisen within the last year in the 
treatment of hypertension (high blood pressure). As a result of funda- 
mental biochemical studies undertaken several years ago, a new and 
highly promising series of drugs is under study in patients with hyper- 
tension. If preliminary studies are supported by more extensive clinical 



- ll. - 

trial these drugs should provide a major improvement in the treatment of 
severe hjrpertension. The biochemical studies vere directed at clarifying 
the mechanisms by which certain physiologically active substances are 
produced and destroyed in the body. As a result of these investigations 
the chemical pathways by which serotonin and epinephrine are produced 
and metabolized were defined and the enzymes (protein catalysts) con- 
cerned were identified. It was found that an enzyme known as monoamine 
oxidase plays a central role in the destruction of these active sub- 
stances and that a number of chemicals have the property of inhibiting 
this enzyme. It was observed that when such inhibitors were given to 
patients, the ability of the individual to regulate his blood pressure 
was impaired and his standing blood pressiire was markedly lowered. 
Drugs with the ability to produce such "postiiral hypotension" have 
been found useful in the management of severe hypertension, and trial of 
active members of the new group of monoamine oxidase inhibitors was a 
logical step. Trial of the most active such agent in Clinical Center 
patients has indicated that, barring the development of unpredictable 
side effects, this drug is a marked improvement over previous drugs 
with similar blood pressure lowering effects since the new drug can be 
given in a single daily dose with continuous and reproducible action and 
unlike those which it may well supersede, it does not produce such unde- 
sirable effects as severe constipation and sexual impotence. 



- 5 - 

The effectiveness of monoamine oxidase inhibitors in hypertension 
is not the only \iseful product of basic research on the metabolism of 
serotonin and epinephrine. The role of these substances in the central 
nervous system control of blood pressure and other "sympathetic functions" 
has been the subject of intensive and productive research. Drugs which 
modify the distribution and activity of these potent chemicals in the 
brain have been found to be very useful in the management of hjrpertension 
and particularly in the treatment of mentally disturbed patients. 

Despite the improvement in the outlook for patients with high 
blood pressure resulting from the development of increasingly effective 
drug treatment, the \anderlying cause of most forms of hypertension re- 
mains obscure and treatment is presently directed largely at the results 
of, rather than the disease itself. Studies directed at improved 
understanding of the fimdamental disturbance are being continued^ 
investigation of several components of the blood (callicrein, calli- 
dinogen, calledein) \daich appear to be present in increased amounts in 
patients with hypertension, are being carried out in attempts to identify 
their nature, function and possible significance. 
Atherosclerosis 

As the underlying cause of coronary occlusion (heart attacks) 
and cerebral thrombosis (stroke) atherosclerosis is the cause of more 
deaths than any other single disorder. Characterized by the deposition 
of fatty materials in the walls of blood vessels, atherosclerosis 



- 6 - 
produces narrowing of the blood channels and predisposes to the formation 
of clots which may completely cut off flow. When this occurs, the 
tissue supplied by the vessel concerned is deprived of oxygen and 
generally does not survive. 

Although considerable advances have been made in recent years in 
our understanding of factors predisposing to the development of 
atherosclerosis, many gaps remain to be filled and adequate and reliable 
means of prevention are yet to be developed. The most fruitful area of 
research appears to be in the study of the handling of fatty substances 
in the body since abnormalities of the concentrations of various fats in 
the blood have been more consistently noted to be associated with the 
development of atherosclerosis than any other disturbance. Rapid ?.3. 
advances have been made in our understanding of the long-neglected 
field of fat metabolism but the picture is far from completed. Contri- 
butions of the intramural research program in the last year have been: 
The development of a highly sensitive and reliable detection device for 
gas phase chromatography - a method for the separation and identification 
of the components of fat mixtures. Fats as they occxir in nature are 
varying mixtures of a number of substances. Since each of these may be 
treated differently in the body, studies in the past have been hampered 
by an inability to consider each component separately. The new technique 
shoiild greatly improve this situation and make progress more rapid. 



- 7 - 

The adrenal hormone, epinephrine, has been found to have two 
distinct effects on fat metabolism. By a direct effect on fatty tissues, 
it causes a release of unesterified fatty acids, the building blocks of 
fatty tissue, to the blood. This effect is antagonized by increase of 
the blood sugar level, and since the latter is one of the actions of 
epinephrine, this effect is self -limited. However, a second more 
persistent effect is a marked increase in the cholesterol -bearing fat- 
protein complexes of blood. This may explain the stress-induced 
elevation of blood cholesterol which has been noted in accoiontants at 
income tax deadlines and students at examination time and coiild con- 
ceivably provide an explanation of what relationship, if any, exists 
between stress and coronary disease. 

Advances have been made in knowledge concerning the source, 
interchangeability and some aspects of the chemical structure of the 
proteins which carry the water-insoluble fats in the blood. 

The search for drugs which can inhibit the manufacture of 
cholesterol in the body has continued. Several such compounds have been 
studied, but as yet none has been found sufficiently free of toxic side 
effects to be considered promising. It is, therefore, not yet certain 
whether this will prove a practical approach to the reduction of blood 
choloesterol and possibly to the prevention or treatment of atherosclerosis. 



- 8 - 
Congestive heart failure 

Hiis symptom complex results from many forms of heart disease 
when the heart muscle is no longer able to produce the forceable con- 
tractions required for the output needed to maintain an adequate 
circtilation. Shortness of breath and water-logging of the tissues 
(edema formation) are the most prominent symptoms. Studies of this dis- 
order, its genesis and management have been particularly concerned with 
two aspects: (1) the normal regulation of the force of heart contraction 
and output and its therapeutic modification and (2) factors responsible 
for the abnormal handling of salt and water by the kidney which leads 
to the formation of edema. 

A new method for measuring the velocity of blood flow makes 
possible the assessment of the time- force (power) output involved in 
heart contraction in intact man. Adapted to the familiar heart catheter^ 
the method employs direct electronic computer technique to integrate two 
pressure measurements to yield a measure of instantaneous velocity 
throughout the heart cycle. 

Studies in experimental animals have shown the force of heart 
contraction to be regulated under normal conditions by nervous control 
responsive to pressure changes in certain arteries supplying the head. 
The very striking effect of these nervous influences on heart con- 
traction have stimulated interest in the possible imitation of these 



- 9 - 
actions with available drugs. The therapeutic action of such drugs 
(andrenergic and norepinephrine types, ) in patients with heart failure 
is being evaluated. 

The abnonnal retention of salt by the kidney which leads second- 
arily to the accumxilation of water and formation of edema has in previous 
studies been shown to be dependent upon increased, secretion of aldoster- 
one, a hormone of the adrenal cortexo However, the sequence of 
mechanisms leading to the increased aldosterone secretion had not been 
clarified* A new link in the chain has now been established in the 
demonstration, by cross-circulation between experimental animals, that 
the secretion of aldosterone is controlled by a new and as yet un- 
identified hormone present in the circulation Of the edema-forming 
animal. Studies aimed, at the isolation and identification of the 
hormone and the determination of its source in the body are under way. 
Surgical app roac hes to heart disease 

Until adequate preventive measures are conceived and adopted 
there will continue to be a sizeable group of patients with anatomi.cal 
abnormalities of the heart whose lesions are at least theoretically 
amenable to surgical correction. This is particiilarly true of con- 
genital and rheumatic heart disease. Since adequate means for the 
prevention of rheumatic fever are available, it is to be expected that 
the number of cases of chronic heart disease resulting from rheumatic 
fever and requiring surgery will decrease progressively. No such 



- 10 - 
decrease in congenital heart disease is anticipated. Meanwhile the 
variety of congenital heart disease (vdiich assumes many forms) amenable 
to surgical treatment is gradually increasing as improved methods are 
developed for substituting for the patient's heart and lungs during 
open-heart surgery and as nev surgical techniques are devised. An im- 
portant part of the surgical approach to heart disease is in the diagnos- 
tic evaluation of patients to determine the nature and severity of the 
lesions. Such infonnation provides answers to three vital questions: 
(1) Is the lesion amenable to surgical correction with present tech- 
niques? (2) Is the lesion severe enough to warrant surgical correction 
at this time or can it await the further improvement in surgical tech- 
nique which is occurring so rapidly? and (3) What operative approach and 
what aiaxiliary techniques such as reduced body temperature and heart- 
lung machine, are required? 

The Heart Institute program in this area has made particularly 
significant contributions to the improvement of diagnostic and evaluative 
procedures. The most important development during the past year has 
been a technique for detecting and quantifying abnormal shunting of 
blood between the left and right side of the heart. Based on the use of 
the radioactive inert gas, krypton^^, the method depends upon the fact 
that this gas is very rapidly taken up by the tissues when inhaled and 
very rapidly given off in the lungs when injected into a vein. Thus 
when it is injected into a vein, its appearance in arterial blood 



- 11 - 

(vhich has since traversed the lungs) is an approximately quantitative 
indication of short-circuiting of the lungs - that is, an abnormal 
communication with movement of blood from the right side of the heart 
to the left. Conversely, if the gas is inhaled, its early appearance 
in the venous blood is an indication of movement of blood from left to 
right heart since all of the venous blood would normally have lost its 
krypton in passing through the tissues. Since such short-circuiting 
movements are common in a number of forms of heart disease and since 
the size and location of such shunts are critical factors in selecting 
surgical procedures, the importance of such techniques is apparent. 

EPIDEMIOLOGY 
The epidemiological approach to the problems of heart disease 
continues to be emphasized in all phases of the Institute program. 
Much data now available is being analyzed and further knowledge will 
undoubtedly help to clarify many of the factors related to heart dis- 
ease. The Framlngham Study, which is really the pioneer effort in this 
approach, continues along its planned course. Investigations of hyper- 
tensive heart disease in this Massachusetts community have produced 
some interesting data. Heart enlargement, which is one of the marks of 
heart damage used in defining hypertensive heart disease, has been shown 
in Framlngham to be evident at all blood pressure levels, even the very 
lowest, but becomes increasingly common as the blood pressure rises. 



- 12 - 

Other studies using the epidemiological approach have been 
developing and are of interest. One, completed this year in North 
Dakota, through the technical assistance program of the Institute— was 
designed to explore the possible relationship of diet, heredity, weight, 
smoking and stress to coronary disease. While this particular study 
failed to reveal any association between diet and coronary disease, it 
should be emphasized that this finding is based on only one study and 
points up the fact that more refined methodology is a constant objective 
of the epidemiologist. In a companion study in Connecticut, emphasis is 
being placed upon the relationship between stress and personality 
factors. Preliminary findings indicate that coronary cases generally 
differ from controls in respect to these variables. 

Progress in epidemiology continues to be made along other fronts. 
The meeting held this past summer in Geneva, supported by a Heart 
Institute grant and sponsored by the World Health Organization is one 
example of the increasing awareness among researchers concerned with 
cardiovascular diseases, of the potential value that lies in this 
community approach to the problems of heart disease. Mention should also 
be made of the Epidemiological Conference scheduled for April, 1959 at 
Princeton, New Jersey, Co-sponsored by the National Heart Institute 
and the American Heart Association, this meeting will bring together 
many of the Nation's top epidemiological Investigators cif cardiovascular 



- 13 - 
disease. These experts will explore and discuss at length, better and 
more refined methods of study, new areas for investigation and a host of 
other problems peculiar to this specialized area. 

RESEARCH GRANTS 

There have been many interesting and promising developments 
during the past year flowing from the laboratories of institutions and 
individual investigators supported by Heart Institute research grants. 
The following are a few of these many achievements, casting new light, 
creating new approaches to some problems of heart disease that still 
remain to be solved. 
Arteriosclerosis 

No single factor has thus far emerged as determinant in the 
etiology of atherosclerosis. Diet, the endocrine glands and genetic 
influences still seem to be in the forefront. Studies of population 
groups suggest that the differing incidence of atherosclerosis among 
various peoples is related to differences in their way of life, Though 
fat metabolism seems Implicated in this disease, there is growing 
reluctance to assign too great importance to dietary fats alone, and more 
recognition is being given to the possibility that the relative amount 
of fat in the diet is at least equally important. 

The ideal drug for consistently lowering cholesterol levels in 
the blood has not been found thus far. However, a veiy real possibility 
exists that such agents, being closely related to cholesterol, may 



- li+ - 

themselves on extended use prove atherogenic. A newer approach lies in 
the direction of finding agents capable of mobilizing cholesterol and 
other lipids from atherosclerotic deposits in the body. The discovery 
of a mechanism to effect this lipid mobilization in rabbits, may develop 
into a real breakthrough in therapy. 

The diagnosis of atherosclerosis centers mainly on determinations 
of blood lipoprotein levels for their prognostic value in large-scale 
screening, in epidemiologic studies and on visualization of coronary 
narrowing. A new method has been devised for determining human serum 
beta lipoproteins. Simple, rapid and accTorate, it requires only small 
amounts of serum and should provide a means for rapid evaluation of 
serum lipoproteins in large populations. Another important diagnostic 
tool is the new technique for visualizing the coronary arteries by 
injecting contrast media into the aorta during induced cardiac arrest 
and total occlusion of the ascending aorta. This method has proven 
safe and effective in animals and is being applied clinically. 

In the surgical treatment of intractable angina pectoris, the 
development of new methods and the evaluation of their effectiveness 
continues. Circulation to the myocardium may now be improved by a 
variety of procedures — chiefly by opening up new intercoronary communi- 
cations. One new surgical procedure to relieve patients suffering from 
severe intractable angina pectoris has been described and although only 
a few such operations have been performed, the survival rate has been 



- 15 - 
high and relief has varied from partial to complete. A set of 
instruments designed for use in this type of surgery is now available 
to the vascular surgeon. 
hypertension 

New clues continue to shed light on the causes of hypertension. 
The relationship between psychological stress and hypertension in 
humans has been further elucidated, particularly regarding the prog- 
nosis of the disease. A five-year study of the environmental aspects 
of the disease has been concluded. A massive amount of data has been 
gathered on the precursors of hypertension among a predominantly Negro 
population composed of medical and nursing students in Tennessee. 
During the first year of a study seeking the reason for the high 
incidence of hypertension in West Indian Negroes, a complete census 
was taken of the population of an area in Nassau and a blood pressure 
survey of a segment of this population was made and compared with 
others of several smaller island populations. It revealed marked 
differences in the prevalence of this disease. 

Prominent among investigations of the medical treatment of 
hypertension is the only long-term run on hexamethonium, a drug whose 
effects have now been observed in a large group of patients for periods 
of up to eight years. Newer drugs continue to be tested clinically but 



- 16 - 
a longer period of time is needed to properly evaluate their usefulness. 
Among these are hydrochlorothiazide, some of the never tranquilizers 
and some monoamine oxidase inhibitors. 

According to a study of the effects of radical dietary treatment 
of hypertension, patients on a stringent rice diet have a survival rate 
of 85 percent during follow-up periods running from 2-12 years, as com- 
pared with a 30 percent survival in those not on this stringent diet. 
Rheumatic fever and rheumatic heart disease 

Studies relating to the prophylaxis of rheumatic fever have 
compared the relative effectiveness of various antibiotics in eradi- 
cating beta hemolytic streptococci in the throats of afflicted patients. 
Although penicillin continues to be the drug of choice, there is some 
indication that low doses of this antibiotic over long periods of time 
in rheumatic fever prophylaxis may be a factor in the dangerous in- 
crease of antibiotic-resistant staph infections. 

In surgery for rheumatic heart disease, refinements in the 
instruments used in the so-called "purse string" procedure have markedly 
improved this operation. As a result it can now be perfonned with 
greater safety and less trauma. On a large group of patients with 
mitral stenosis, statistical analysis is now underway with respect to 
such factors as survival, degree of improvement and effectiveness of 
operative procedure. In the condition known as aortic stenosis, the 
introduction of a new surgical procedure to correct it, has resulted 



- 17 - 
in a 10 percent decrease of operative mortality. Of those vho survive 
the operation, about 70 percent have shown very substantial improve- 
ment. 
Cerebrovascular and peripherovascular disease 

Although the problems of cerebrovascular and peripherovascular 
disease include the problems of atherosclerosis in general, special 
activities in these areas deserve particular attention. Data from 
a large series of autopsies reveal that males are more predisposed to 
cerebral thrombosis than females. But this male predisposition is not 
nearly so marked as that which occurs with coronary thrombosis. Male 
predisposition to cerebral thrombosis appears to decrease in the older 
age groups. The same is true of coronary thrombosis. Now in progress 
is a long-term follow-up study on patients with cerebral thrombosis in 
whom treatment with various natural and synthetic estrogens is being 
evaluated, and on whom new estrogens will be tried as they appear. 
It has not been feasible to apply the new techniques of vascular 
surgery to cerebral vessels, mainly because of the small size of certain 
intracranial vessels and the difficulty of maintaining flow without 
thrombosis. An original and imaginative approach to small vessel 
anastomosis in cerebral circulation now in progress, seeks to create 
additional techniques or adapt some already devised for treating cerebro- 
vascular disease. 



- 18 - 
Congenital heart disease 

During the past year^ congenital cardiac malformations were 
produced in rats by exposing their pregnant mothers to an atmosphere 
of 6 percent carbondioxide during the period before visible growth 
from the primitive cell layers had begun. This is the first time that 
congenital heart lesions have been produced in this way and marks an 
important advance in understanding the causes of congenital heart 
disease and in having a way of producing these lesions for further 
investigations. 

A marked improvement in conventional angiocardiography has been 
achieved by observing that this technique, used in conjunction with 
induced cardiac arrest, will now permit demonstration of the position 
and size of certain congenital defects not otherwise detectable. This 
new technique may complement or even supplant cardiac catheterization 
in the diagnosis of certain congenital cardiac lesions. 
Surgery 

A number of advances in heart surgery, as they have been used 
in arteriosclerosis, hypertension and congenital heart disease have 
been described. Others, with more general application to cardiac 
disease should be noted here. 

Improvement in methods of circulating the blood outside the hioman 
body continues to be made. The effects of coagulation factors and 
changes on the electroencephalograph have been emphasized on a continuing 



. 19 - 

basis. It has been found that the irregular beating of the heart which 
occurs during hypothermia, can usually be prevented by coronary per- 
fusion with whole blood. This technique has been used on patients 
undergoing open heart surgery and the results have been very satisfactory. 
In animals, it has now been found possible to cut into the left 
ventricle of the heart for better exposure of certain structures with 
satisfactory healing of the incision. Several instances of life- 
saving kidney transplants into a uremic twin, have been reported, and in 
one instance, a human twin recipient has completed a successful preg- 
nancy. Progress has been made in the development of an artificial lung 
which gives promise of greater efficiency than those in current use. 
Prototype models of artificial kidney and heart pumps for permanent 
implanting have been made and experimental use of these machines in 
dogs, continues to yield promising results. 
Epidemiology and geographic pathology 

The study of man in his environment and of disease in human 
communities continues to be a principal phase of the Heart Institute 
research grants program. Quantitative methods have been developed for 
measuring the degree and location of arteriosclerotic lesions in their 
various stages of development and for collecting, preserving and storing 
the specimens themselves. Work done in this country has given rise to 
similar studies in Puerto Rico, Columbia, Costa Rica and Guatamala. 
Other foreign population groups, studied from this point of view, 



- 20 - 
include various groups in Korea, Jamaica, Israel, Nigeria, Rome and South 
Africa. In this country, a number of racial, occupational and socio- 
cultural groups in several widely scattered areas are currently "being 
studied. Worth particular mention in this general field are: com- 
pletion of a study of a large kindred population in Michigan with a 
high frequency of hypercholesteremia and xanthomstosis, which throws 
new light on the mode of inheritance of serum cholesterol levels and 
reaffirms the association between hypercholesteremia and coronary 
disease; a large-scale study now in progress to evaluate the work per- 
formance of patients with cardiovascular disease; completion of the 
first 19 months of a three- to six-year pilot study to evaluate hospital - 
based home medical care services in the treatment of congestive heart 
failure; and an analysis of the distribution of trace metals in human 
beings as determined on autopsy material from adults dying of various 
causes in the United States, Switzerland, Nigeria, Belgian Congo, India, 
Japan, Thailand, Hong Kong, and Formosa. This project seeks to corre- 
late cardiovascular renal disease with metal patterns in the kidney and 
heart . 

TRAINING 
Better teachers and improved methods of teaching have long been 
recognized as fundamental to a productive and meaningful approach to 
cardiovascular disease. Ten years' experience in the support of under- 
graduate and graduate training has in every way been a wise investment. 



- 21 - 
One direct result is that today's physician is better trained than his 
predecessor of only a fev years ago. Today's medical students are 
becoming more attracted to careers in medical research because of new 
opportunities for participating in the research activities of their 
schools. More comprehensive training in the clinical and public 
health aspects of cardiovascular disease is a direct result of the 
Heart Institute training programs. There are now 102 medical schools, 
schools of osteopathy and schools of public health receiving support 
for the training of undergraduate students in research and scientific 
methods . The graduate training program has been expanded and it is 
anticipated that by the end of the current year, there will be at least 
180 training programs receiving support. This will represent an in- 
crease in the number of people being trained from 395 in 1958 to some- 
thing over 600 in 1959. 
Research fellowships 

This program offers financial support to qualified scientists 
and promising students and is a vital part of the Heart Institute's total 
research effort. Stepped up as a resiilt of this year's increased appro- 
priations, the program anticipates the award of about 100 predoctoral 
fellowships. By the end of the current year, the Institute will 
have made about 175 postdoctoral fellowship awards. In addition, about 
50 special fellowships were given to outstanding young men during the 



i 



- 22 - 
past year. Because of special programs in comparative cardiology, 
genetics and drug development, the number of applications for special 
fellowships continues to show a substantial rise. 
Conferences 

Greater emphasis is being given to the support of scientific 
conferences both in this country and abroad. These conferences are 
extremely valuable for stim\ilating research and scientific activity, 
particularly where known gap areas exist. One example is the meeting in 
Rome this past fall of the International Committee on Blood Clotting 
Factors, made possible through a Heart Institute grant. Here were 
gathered experts from about twelve nations concerned with the numerous 
technical and practical problems arising from the clinical management of 
coagulation disorders. Another example of this kind of activity was 
the symposium held at the Heart Institute on the subject of epinephrine 
and its chemical relatives, including serotonin. While this general 
subject is by no means new, there has been a strong resurgence of 
interest because of the recent discovery that tranquilizers, important 
in the treatment of hypertension and mental illness, exert their effects 
through a mechanism which involves these substances. 

These conferences can be measured in terms of tangible results, 
particularly with the subsequent publication of the conference 
"proceedings". These have grown in volume and represent the 



- 23 - 
contributions of many people engaged in research in a given field. As 
such they constitute a valuable compilation of current knowledge and 
experience for use by scientists everywhere. 

HEART DISEASE CONTROL 
The chief source of technical assistance to the States in matters 
pertaining to diseases of the cardiovascular system is the Heart 
Disease Control Program. During the past year the number of medical 
officers assigned to State and local health departments to develop new 
heart disease control activities rose to 22. These trained physicians, 
on loan assignments to State and local health departments, are engaged 
in developing, improving and expanding community heart disease control 
programs. The application of knowledge to reduce rheumatic fever deaths 
and disability continued at a high level during the year. At least six 
new rheumatic fever prevention programs were begun during the past year 
in States and cities throughout the country. One interesting development 
was the experimental initiation in several States and communities of a 
fluorescent antibody technique developed by the Communicable Disease 
Center for rapid identification of "strep" infection. It is now hoped 
that the eventual eradication of rheumatic heart disease may be closer 
at hand if this technique can be perfected and its use made widespread. 
Progress in rheumatic fever control was made in other ways during the 
year. Of interest is the preparation of a rheumatic fever record 



L 



- 2k - 
guide for assisting States and localities to establish registers, 
simplify their records and serve patients and the program more 
effectively. 

In attempting to expand the already growing interest in the 
problem of cerebrovascular disease, the Heart Disease Control Program 
initiated a project with the Georgia State Health Department to establish 
a comprehensive "stroke" rehabilitation program on a State-wide basis. 
It encompasses education, demonstration, research and rehabilitation. 
The demonstration phase consists of a cerebrovascular facility at the 
Grady Memorial Hospital in Atlanta under the sponsorship of the Atlanta 
Health Department, Emory Medical School, Georgia Heart Association, and 
the Georgia State Department of Health. 

In the area of congenital heart disease, the Control program 
cooperated with the Chicago Heart Association in developing a tape 
recorder for the rapid screening of school populations to detect this 
disease by means of listening to abnormal heart murmers on the recorder. 
Wow developed, the recorder will be tested in a large field study 
during the coming year. Several Program physicians working closely with 
health departments have been seeking to determine if a relationship 
exists between Asian flu--as well as other viruses--and congenital 
malformations of the heart. One large study in New York, stimulated by 
the Control Program, and supported by the National Heart Institute, is 
studying virus diseases in the etiology of congenital heart disease, 
using as a base the sera of women with Asian influenza. 



- 25 - 

Another project completed during the year involved the screening 
of a large population of school children in Colorado; comparing one-lead 
electrocardiograms, the X-ray and physical examination as methods for 
early diagnosis of congenital heart disease. The results showed that the 
electrocardiogram and X-ray were inadequate for this purpose, when com- 
pared with a physical examination using the stethoscope. 

CONCLUSION 

The National Heart Institute completed its tenth year of 
existence during 1958 - to be precise, on June lUth. The advances 
made against heart disease since the Institute's birth in 19^8 have 
been many and they have been quite remarkable- -far beyond the expec- 
tations of the authorities in the field at that time. As members of 
this Committee are aware, a number of the particular research accomplish- 
ments have been dramatic. They have stirred the hopes of our people. 
They include such noteworthy accomplishments as the development of the 
artificial heart and lungs for life-saving surgery to correct heart 
defects, the use of natural and synthetic blood vessel grafts and 
prosthetic devices in operations for repair of congenital malformations 
and acquired heart damage, the means of prevention of rheumatic fever 
recurrences and subsequent rheumatic heart disease by treating the pre- 
ceding streptococcal infection with antibiotics. These highlights have 
been paralleled by others- -less spectacular, less dramatic but which 
today permit better recognition, improved methods of treatment and more 
intelligent management of those afflicted with heart and blood vessel 



- 26 - 
disorders. They include the development of new diagnostic methods, new 
surgical techniques and new therapeutic agents and procedures. This 
progress in research has resulted in expanded clinical application and 
there have been considerable advances in basic knowledge in many areas. 
We now know a great deal more about normal and abnormal functioning of 
bodily mechanisms and of processes inherent in the development of 
cardiovascular disease. Of course, much of what we know represents 
isolated bits and pieces of knowledge, yet these bits and pieces con- 
stitute the raw materials out of which will come the foundations for 
future progress. 

I have mentioned some of these developments that have occurred 
during the past decade by way of expressing to this Committee a large 
measure of gratitude for its support of the National Heart Institute 
programs . It is a truism to say that without the support of this 
Committee, representing as it does the citizens of this Nation, our 
research effort into diseases of the cardiovascular system would still 
be in its infancy. We have a long way to go. But we have come a long 
way, too, thanks to the wisdom, the foresight and the abiding interest of 
this Committee. 



f-^'^^e^ 



^--v^^ 



SUMMARY OF OPENING STATEMENT 

■by 

. Chief Dental Officer 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 
for 
"Dental Health Activities" 



Mr. Chairman and Members of the Committee: 

There are currently over I70 million people residing in these 
United States, 95 percent of whom have, or will have need of dental 
care. Those that avail themselves will spend 1.7 "billion dollars for 
this service in the coming year. Against this gigantic health problem, 
there is a force of about 90,000 practicing dentists. In 1975 our 
population will swell to an estimated 228 million people and we shall 
need 170,000 dentists merely to meet the newly rising demand for dental 
care. Even if we build all of the projected new dental schools and 
expand existing facilities, the estimates are that the population per 
dentist will further increase. 

It is against this background that the opening statement is 
presented in support of the Dental Health Activities of the Public 
Health Service. These activities are directly concerned with: 
fundamental research on the cause and prevention of oral diseases and 
related conditions, incltiding support of research projects and training 
grants to non -Federal institutions; the development of dental resources; 
and, furnishing consultant and technical assistance to State and local 



- 2 - 

dental programs. The budget proposal before you requests an appropria- 
tion of $7,420,000 for support of these activities in I960 which is 
the same as the 1959 appropriation. 

Programing for research at the Dental Institute in 196O is 
designed to enable a beneficial review of current programs, while 
pointing toward occupancy of its new research building in November I960. 
In ensuing years, the provision of these modern, and more adequate 
laboratory facilities will afford greater opportunities for the 
Institute staff and will attract, in increasing numbers, outstanding 
visiting scientists from both the United States and foreign coiintries. 
While continuing to assume a major responsibility for carrying out 
fundamental research on specific oral diseases such as caries and 
periodontal disease, the research program in I96O will give increasing 
a.ttention to fundamental, non-disease oriented studies primarily in 
the biophysical and biochemical field. Representative among such 
programs is the study of the dibasic phosphate compounds which show 
promise as an effective dietary control of dental caries. Clinical 
trials with one of these compo\ands are scheduled for I96O. In the 
field of protein biochemistry, evidence is now available which shows 
a relationship between protein and dental caries, i. e., lysine 
deficiency which is conducive to experimental dental caries. Unlike 
the presumed local action of carbohydrates and phosphate minerals the 
beneficial effects of lysine seem to be mediated through some extra- 
oral systemic activity. 



- 3 - 
Further, in collaboration with the Interdepartmental Committee on 
Nutrition for National Defense, epidemiological and biometric studies 
have recently been conducted in Alaska and Ethiopia and will be extended 
this year to other foreign countriec. These studies are contributing to 
a better understanding of oral disease patterns especially of periodon- 
tal disease, the main cause of tooth loss in the United States beyond age 

In the field of microbiology, studies begun during the past two 
years using germ-free animals will be emphasized. These efforts in 196O 
will be concentrated on an evaluation of selected pure strains of oral 
bacteria and their possible relation to dental caries. 

In the extramural programs of the Dental Institute, grant awards 
will continue in i960 at essentially the same level, with emphasis in 
the fields of oral, systemic and chronic disease relationships, cleft lip 
and palate, periodontal disease and aging. Increased interest in the 
fellowship and training grant programs is indicated in the coming year. 
Reflected in this is the increased awareness by the dental profession of 
the immediate and projected need for more teachers and research workers 
oriented in the dental sciences. It is primarily through the dental 
training programs that ituch of this need viill be met. 

In the area of Dental Public Health, efforts toward the fluori- 
dation of communal and non-communal water supplies continued to receive 
considerable attention in 1959* Although measurable progress has been 
made in the larger cities, 95 percent of the almost 15,000 smaller 



- k - 

cotranunitles still have not adopted this effective caries control measure. 
At the individual level more than one-third of the United States population 
no\T consumes water obtained from other than communal soiirces. To meet 
this special need, simple and practical methods for home fluoridation have 
heen developed and subjected to limited field testing. Efforts to stimu.late 
private enterprise in making home fluoridation equipment and services 
available to the general public will continue in 196O. Other represent ive 
activities of the Division in 1959 included the study of oral disease 
in relation to national occurrence in various age, sex and cultural 
groups. Currently, emphasis is being placed on studies among the chronically 
ill and aged, the mentally ill, and handicapped individi^als. 

A reservoir of professional skills, more effectively used, con- 
tinued in 1959 to be a prime objective of our Division of Dental Resources. 
During the past year, the Division added another to its series of regional 
manpower studies which are designed to assist State and local groups in 
planning for needed school expansion. A fourth survey is now under way 
covering the Great Lakes region. Current estimates indicate we would 
need 250,000 dentists working for ten years to eliminate the present 
backlog of dental care. Consideration of this present and projected 
dental manpower shortage led some two years ago to the initiation of studies 
involving the expanded use of aiixiliary personnel such as chairs ide 
assistants and dental hygienists. These studies already indicate that the 
use of such personnel by practitioners permits a significant increase in 



k 



- 5 - 
patient load per dentist. Also xmder study during the past year were a 
variety of dental prepayment plans serving specific population groups. 
Activities such as these are part of the Division's continuing program 
to develop and make available information which will help voluntary pre- 
payment programs to become established on a soxind basis. 

In conclusion, it can be said that 1960 is the year in which our 
Dental Health Activities will be primarily concerned with continuing 
the ongoing programs pointing toward strengthening activities in the most 
promising areas of dental research, resources and public health in 
ensuing years. 



L 



OPENING STATEMENT 

Chief Dental Officer 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 
for 
"Dental Health Activities" 



Mr. Chairman and Members of the Committee: 

This statement is presented in behalf of those activities of the 
Public Health Service concerned with the prevention, control and treat- 
ment of diseases and abnormal conditions of the oral cavity. The 
budget proposal before you requests an appropriation of $7^^20,000 for 
support of these activities in I960. This is the same as the 1959 
appropriation, but is $2,000 greater than the 1959 obligation plan. 

The universal affliction of dental disease and the accompanying 
financial burden now borne by the American people has been brought to 
the attention of this Committee on previous occasions. This appalling 
physical and financial burden is further aggravated by a popiilation 
growth of 3 million persons a year creating a situation which demands 
an increasing number of dentists and auxiliary personnel. While the 
total number of qualified dentists has increased in the last three 
decades, the total population of the coxontry has increased at an even 
greater rate. To attack this problem solely in terms of increasing 
the supply of dentists would be unrealistic and would fall well short 
of the desired goal. Recognition of this fact has led to the initia- 
tion of studies involving the expanded and more effective use of 



- 2 - 
auxiliary dental personnel, such as chairside assistants and dental 
hygienists. These studies indicate that utilization of such personnel 
permits a significant increase in patient load per dem-tist. 

At the practical level, dentistry today faces a major public 
health probl«n with respect to the chronic and prevalent diseases of 
an aging population (65 years and older) that is expected to increase 
frcan 15 million to 21 million by 1970. Through programs of public 
education and through the develojanent of resources for dental manpower 
we shall continue to impress upon oxxc people the need for continued 
dental protection, the importance of good oral hygiene, and the vital 
role of nutrition in the maintenance of oral health. However, despite 
the unquestioned importance of these efforts, they are but stop-gap 
measures in a broadening attack to solve the many still remaining prob- 
lems of oral disease etiology. 

A few years ago, investigators in the dental sciences working 
alone in small laboratories could, and in fact did, make significant 
discoveries using relatively simple, inexpensive equipment. While this 
is still possible in certain fields, the long-range, successfxil explora- 
tion into the etiology of oral disease requires knowledge drawn from all 
of the basic sciences and depends increasingly on the collaboration of 
groups of scientists working together with more refined instruments and 
expanded research facilities. 



- 3 - 

Prominent among the characteristics of fimdamental research in 
dentistry is the enormous complexity of the oral environment which, in 
turn, reflects the magnific complexity of the human body. Furthermore, 
as we gain new knowledge of oral biologic systems and their interrelation- 
ship with the whole body we find our problems multiplying and becoming 
even more complex. This is the price we pay for learning. 

This year heralds the beginning of the second decade of research 
by the Nationsl Institute of Dental Research. The discovery dxiring the 
early years of research of the highly significant relationship of 
fluoride in drinking water to dental caries and its rapid adaptation 
to public use is without doubt the most significant development in 
the history of preventive dentistry. After more than a decade of 
study by the National Institute of Dental Research, beneficial results 
are not only continuing to be evidenced in children born subsequent to 
fluoridation, to the extent of 6O-65/0 reduction in dental caries, but 
also in children whose teeth had already calcified before the beginning 
of fluoridation. Thus, although dental caries continues as a major 
health problem, each passing year sees progressive benefits to commu- 
nities with fluoridated drinking water. As of January 1, 1959 a 
total of 3^^699^356 persons in 1,7^2 communities were drinking water 
routinely fluoridated. 

Despite the unchallenged value of present-day caries -control 
measures, still more imaginative concepts will be required if the 



- u - 

ultimate goal of prevention of oral disease is to "be achieved. Ten years 
ago space exploration was considered by many to be an imaginative dream; 
yet today we see it as a reality. Similarly- -the phenomenal progress of 
dental research in recent years demands of us that constant reappraisals 
be made of the past and current concepts. For example, there is today 
limited data from our laboratories which indicates that dental caries 
is closely related to a transmissible bacterial flora and that it might 
therefore be considered a contagious disease imder certain conditions. 
A further finding of significance is that animals totally free of 
bacteria, i. e. germ-free rats and hamsters, are also free of dental 
caries. On the other hand, no such evidence is yet available on the 
subject of tartar formation. Since current concepts hold that the 
microorganisms normally inhabiting the mouth are primarily responsible 
for calculus deposits and that these formations, in turn, provide the 
initial irritant in the sequence of tissue changes leading to pyorrhea, 
the questionable role of bacteria in the etiology of calculus becomes 
most important. 

In programing for i960, the Dental Institute has endeavored to 
provide support only for those studies most likely to realize the objec- 
tives of improving the oral health status of the Nation. Such programing 
will, while serving to prepare the Institute for the transition period 
related to occupancy of the new dental research building in November 196O, allow 
a beneficial review of our ongoing programs pointing towards expansion 



- 5 - 
into the raost promising areas of research. In ensuing years, the pro- 
vision of modern, adequate laboratory facilities will measurably enhance 
the stature of our Institute and will attract, in increasing numbers, 
outstanding visiting scientists from both the United States and foreign 
countries. The encouragement and support of such collaborative research 
ventures and the reciprocal assignment of National Institute of Dental 
Research scientists to various research centers should bring mutual 
benefit to all participants and contribute to earlier major break- 
throughs in the oral health field. 

While continuing to assTJime a major responsibility for conducting 
fundamental research on the specific oral diseases related primarily to 
cause, control and eventual prevention, the National Institute of Dental 
Research program of research in I960 will give increasing attention to 
basic, non-disease-oriented studies primarily in the biophysical and 
biochemical field. Formulating plans on the basis of research accom- 
plishments during the current year, the direction and support of future 
activities will necessarily be proportional to their demonstrated 
productivity, importance to the oral health field, and facilities and 
personnel available. In this manner, strength will be concentrated for 
expansion in certain areas, whereas others, as progress justifies, will 
either be maintained at current levels or curtailed. 

In the field of research grants, major shifts in emphasis for 
the use of 1959 funds have been made, as recommended, for specific 



. 6 - 
research areas concerned with oral health. Awards for research projects 
continue with emphasis in the fields of oral -systemic and chronic 
disease relationships, epidemiology, periodontal disease and aging. 

A brief description of the dental health programs in 1959 and 
plans for their continuation in I960 are included in the following 
pages. 

GRAOT PROGRAMS 

Research projects 

Funds made available in 1959 were expended largely for the 
purpose of extending, on a broader and firmer base, the support of 
those institutions and individuals who had received grants in prior years. 
Continued emphasis on such representative programs as periodontal 
disease, oral manifestation of aging, cleft palate and speech pathology, 
dental public health, etc. is indicated in the coming year. 

A shift in emphasis in the design of dental research projects 
continued to manifest itself dioring 1959 as a broadening concept under 
which research teams composed of clinicians, biometricians, public 
health personnel, and scientists in the basic disciplines attacked the 
problems of oral health not only as a physiological consideration, but 
also from the standpoint of oral-systemic relationships and as a condi- 
tion which relates to the social, economic, and educational order of a 
community or geographic area. 



- 7 - 

The Increased number of research projects, from 292 in 1958 "to 
an estimated 32? for 1959 represents participation by almost all of the 
Nation's dental schools, in addition to other scientific or academic 
institutions. Analysis of all projects indicates that the large majority 
of these continue to emphasize research in the basic sciences such as 
biochemistry, microbiology, genetics, pathology, nutrition, and growth 
and development, as related to oral disease. 
Research f e3 lov ships 

Continuation of the fellowship program in 1959 as an integral 
part of the overall grant supported programs has shown it to be a most 
effective mechanism for offsetting the shortage of qualified research 
workers oriented in the dental sciences. 

Awards during 1959 were distributed among 57 institutions in 
27 States, the District of Columbia, and Puerto Rico, with all but one 
of the Nation's dental schools now participating. Among the 51 graduate 
fellowship awards, 11 were concerned with research utilizing clinical 
disciplines (orthodontia, periodontia, oral surgery, pedodontia and 
operative dentistry), while kO were primarily oriented toward training 
in the basic biological sciences. 
Training grants 

The graduate research training program is designed to produce 
greater research potential in the Nation's dental schools. Through the 
support of research training centers for dental graduates, not only is 



- 8 - 
greater competence in research operations being achieved, hut the value 
of research in meeting oral health problems continues to be more forcibly- 
presented to undergraduate dental students by faculty trained \inder this 
program. 

Since the inception of the program in 1957^ the newly established 
research training centers have demonstrated steady progress in meeting 
the acute shortage of professional dental personnel trained to engage 
in research or teaching. Fui*thermore, the funds used to date have shown 
that there are an increasing number of dental graduates each year who 
are enthusiastic about preparing for a career of research or research in 
conjunction with teaching. 

RESEARCH AT BETHESDA 

Dental research at Bethesda is best demonstrated through its broad 
approach to a comprehensive understanding of the cause and control of 
oral disease and re2-ated disorders. Principal investigators representing 
such diverse scientific disciplines as biochemistry, bacteriology, gene- 
tics, oral pathology, epidemiology, histology, and biophysics are 
individually and collectively opening new avenues of knowledge in both 
the dental, as well as the medical sciences. Working in concert with 
laboratory personnel, dental clinicians seek to encourage the clinical 
application of basic laboratory findings as they might relate to cause, 
diagnosis, and treatment and prevention of oral disease. 



- 9 - 

In i960, attention will continue to be directed toward amplifi- 
cation of those research areas showing greatest promise. Included among 
these are the following: 
Studies on the nutritional aspects of oral disease 

The study of nutritional factors relating to the cause and 
control of dental caries continued to make significant progress in 1959* 
Representative among this program is the study of the dihasic phosphate 
compoTjnds as a dietary control of dental caries. 

Recent nutrition studies with Swedish children, extensive National 
Institute of Dental Research studies with white rats, and similar studies 
of other investigators have provided evidence of a direct relationship 
between certain mineral phosphates and a significant reduction in dental 
caries. A better understanding of this relationship and its possible 
application as a dental public health measure will be explored by 
clinical tests in I960. Cooperating with the Dental Institute in this 
study are the National Institute of Arthritis and Metabolic Diseases, 
the Division of Indian Health, and the Bureau of Indian Affairs. 

Other aspects of the influence of nutrition on dental caries, as 
mentioned before, are being carried out in the field of protein biochem- 
istry. For example, evidence is now available which shows a relationship 
between protein and dental caries, i. e. lysine deficiency which is con- 
ducive to dental caries suggests a condition of abnormal relationship or 
imbalance of essential amino acids in diet. Unlike the presvimed local 



- 10 - 
action of phosphate minerals in reducing dental caries, the "beneficial 
effects of lysine seem to be mediated through some extra-oral systemic 
activity. 
Epidemiological approach to the study of periodontal disease 

Although the onset of periodontal disease may occur early in life, 
its onset is insidious and its destructive progress so slow that major 
health damage is usually delayed to middle and later life. Current 
studies show that "by age k3, one out of two persons are affected by 
periodontal disease and that about one person in six requires definitive 
periodontal treatment, extraction of teeth, or both. 

The expansion in 1959 of epidemiological and biometric studies 
to include various popiHation groups in this country, as well as in 
India, Alaska and Ethiopia, is contributing not only to a better under- 
standing of oral disease patterns of prevalence and severity, but also 
to the further development of improved testing methods and treatment of 
periodontal disease. 

For instance, in India it was found that considerably more advanced 
gingivitis exists at earlier ages than in the United States. In the 
Alaskan study, preliminary examination of more than TOO Eskimos has 
revealed significant data. In comparing the prevalence of oral disease 
in individuals living under relatively civilized conditions with that of 
men from primitive villages, it was found that many of the latter were 
essentially free of both dental caries and periodontal disease. Early 



- 11 - 

findings seem to indicate that when Eskimos have lived for some time 
under relatively civilized conditions, the prevalence of oral disease 
increases to a point quite comparable to the average adult male popula- 
tion in the United States. Data now heing collected under different 
environmental conditions but from similar popiilation groups in Ethiopia 
promises greater insight into the influence of nutritional and envi- 
ronmental factors on oral health. 

Recognizing the increasing physical and financial burden imposed 
by periodontal disease and the urgency of mounting a broadened research 
attack on this major health problem, the Dental Research council is now 
studying ways and means of providing more effective support and expanding 
the clinical and basic research teams located within the dental schools 
and other non-Federal institutions in this country and abroad. 
Microbiological studies 

The magnitude and complexity of the oral microbial flora has long 
stood as a natural barrier in the study of the suspected causal relation- 
ship of bacteria to diseases of hard and soft tissues of the mouth. 
Recognizing the great potential of germ-free animals as a research tool 
Ideally suited for studies in oral microbiology, the National Institute 
of Dental Research initiated a limited program in 1959 applying this 
technlc to the study of the etiology and mechanism of carles, tartar 
formation, and periodontal disease. 



- 12 - 

It is now well established that germ-free rats do not develop 
caries even when maintained on diets which consistently produce severe 
caries in conventional animals. In preliminary studies by National 
Institute of Dental Research scientists, dental caries has been success- 
fully produced in germ-free animals by inoculating their oral cavities 
with a single pure strain of bacteria (streptococci) originally isolated 
from carious rats. The characteristics and severity of the resulting 
carious lesions were comparable to those seen in conventional animals. 
These findings, preliminary in character, suggest that this family of 
bacteria, together with others, hitherto ignored in considerations of 
caries etiology, warrant further stiody. 

With reference to the incidence of pathogenic or potentially 
pathogenic fungi from various sites within the oral cavity, significant 
studies in the Laboratory of Microbiology have led to the isolation of 
an unusual and hitherto little known organism 'kno\m as the Leptotrichia 
buccalis . Essentially anaerobic, branching and filamentous in form, 
these organisms are being evaluated by investigators at both the National 
Institute of Dental Research and at Duke University School of Medicine 
to determine their specific identity, nat\ire, taxonomic position, path- 
ogenicity, and significance in relation to caries and tartar formation. 
Histology and pathology 

Productive utilization of electron and X-ray microscopy in basic 
studies of the ultra structure of the mature calcified tissues, cellular 



- 13 - 
changes in growth and development, the mechanisms of calcification, and 

the effects of fluoride and related compounds on tooth enamel continued 

in 1959 "to add new and significant knowledge to the field of dentistry. 

Scientists in the Laboratory of Histology and Pathology reported some of 

their work in a recently published atlas reporting on one of the first 

embryological studies made at the electron microscope level. The report 

is a comprehensive treatise that extends beyond the area of histogenesis 

of dentin in illustrating the several structural changes landergone by a 

group of cells dxiring their differentiation. In addition, it depicts the 

subsequent alterations that accompany the tissue forming activities of 

these cells. Because of its unusual breadth and systematic approach to 

a better understanding of dental histogenesis, this publication is 

proving to be of considerable interest to teachers in the dental and 

basic sciences as well as researchers. 

Additional histological studies of possible diagnostic importance 
relating to the application of new histochemical methods for studying 
protein and enzyme components of oral tissues were continued during the 
current year. 
Clinical research 

As clinical research enters into a number of impoirtant areas, 
efforts related to the evaluation of dental treatment procedures will be 
emphasized. These activities will include experimental and clinical 
analysis of physiological response of teeth to high speed cutting 
instruments used in operative dentistry, a study of physiologic response 



- li+ - 

to dental anesthetic agents, the formulation of improved principles of 
design in maxillofacial prosthetics, diagnostic and etiological stiidies 
of chronic and acute stomatitis, and histochemical studies of oral tissus 

With an already extensive background of experience in genetic 
studies, the Dental Institute plans to initiate additional population 
group studies similar to that currently under way in Maryland. During 
1959^ a two-year study of 5^000 offspring of first cousin marriages was 
begun in Japan in part through the support of National Institute of 
Dental Research and also with the collaborative sponsorship of the 
National Research Co\ancil and the University of Michigan. Unusual 
opportunities are thus afforded for assessJLng the effects of this type 
of inbreeding as compared with the continuous type characteristic of 
the isolate population group now under study in Southern Maryland. 

In a demonstration of how dental research studies can contribute 
to the broad field of health, the H\iman Genetics Section of the Dental 
Institute recently announced the development of a method for the pre- 
diction and early detection of glaucoma disease through study of 
inheritance patterns among kindred of infected individuals. Based on 
observations made during stiidies of herditary defects in dental tissues 
it was found that if an individual has an inherited disease, examination 
of the kindred may reveal additional examples of the disease and thus 
increase the effectiveness of screening procedures. Further, if the 
mode of inheritance is dominant, as with glaucoma, one can acciirately 
trace the affected individuals through family history and home visits. 



- 15 - 
and thus identify the sitship that should "be examined. Diiring the 
early stages of a current dental examination program of the isolate 
population group in Maryland, two patients were found to have chronic 
glaucoma. A family history of eye disease was ohtained for each, and 
the sihshlps in which glaucoma was most likely to occur was established. 
Examination of the selected kindred revealed five cases of frank glaucoma 
and one glaucoma suspect. Two of the patients were discovered before 
they were aware of any eye trouble. Additional studies on other families 
have shown that relatives of affected patients frequently have the 
disease. Detection tests now being offered by the Prevention of Blind- 
ness Society have shown this method of screening, developed by the Public 
Health Service, to be an effective and practical measure for case finding. 

DENTAL PUBLIC HEALTH 

Today, the State and local health agencies across o\ir Nation have 
a major responsibility for coping with the oral disease problem of an 
expanding and aging population. The Division of Dental Public Health 
carries out a fo\ir-fold technical assistance program to stimiilate and 
support these efforts. It includes: (l) identifying the dental disease 
problem on a national basis; (2) developing procedures which can be used 
to prevent and control dental diseases; (3) promoting the utilization of 
the procedures developed; and, (4) training. 
Identification of the dental disease problem 

Identification of the national dental disease problem is a 
continuing activity through which dental diseases are studied in 



- 16 . 
relation to their occurrence in various age, sex or cult\iral groups 
throughout the Nation. Through surveys conducted in many States, 
largely by regional office dental staff working cooperatively with 
representatives from State and local health agencies, the extent of 
dental caries as it occurs in different age and racial groups is 
becoming increasingly well documented, thereby providing a firmer base 
for planning and measuring effectiveness of control programs. Currently, 
emphasis is being placed on studying dental diseases among the chron- 
ically ill and aged, the mentally ill, and handicapped individuals. 

Development of procedures for use in preventing and controlling 
dental disease 

Applied research is carried out by the Division in order to 

develop and improve procediores useful in preventing and controlling 

dental disease. This research ranges from studies of various tooth 

decay preventives such as sodium and stannous fluoride to studies of 

methods for organizing dental health services for the chronically ill 

on a community-wide basis. Applied research activities, for example, 

continue to stress the development of simpler, more efficient and less 

costly fluoridation and defluoridation processes. Better methods for 

testing the fluoride concentration of water have been developed to a 

point where fluoridation installations in the near future may be 

controlled through automation with greater precision than is possible 

using manual methods. 



- 17 - 

Dental care studies of the chronically ill and aged, initiated 
in 1957^ already give evidence of great potential value. From the first 
conmrunity-wide study of the dental service needs of homebound and 
institutionalized, chronically ill and aged persons "being carried out 
by the Division in Kansas City, valuable infonnation has been obtained 
on the dental treatment needs of this group; treatment technics for 
those whose dental treatment is complicated by severe physical or mental 
illness are being worked out; administrative problems concerned with 
locating these groups and financing and providing care are being 
identified; and, prototypes of special equipment needed for treating 
the homebound or bedfast are being developed. 

Since so many dental disease preventive and control measures 
(tooth brushing, dentist visits, proper diet) require the continuing 
personal participation of individuals throughout their lives, studies 
are being conducted to identify some of the underlying reasons why 
individuals either do or do not avail themselves of dental services or 
adopt preventive health practices. One major field study of the health 
attitudes and behavior of individuals has recently been completed by 
the Division in New York State. Data gathered from this and succeeding 
studies will enable a more complete understanding of those motivating 
factors which cause people to carry out, or fail to carry out, recom- 
mended health practices. 



- 18 - 

Promotion of dental public health measures 

For the past several years, a major activity of the Division has 
been the provision of consultation and technical leadership to State and 
local health departments and community groups in a direct attack on the 
tooth decay problem in the United States. Through a cooperative 
national-State -local effort, continuing efforts are being made to 
achieve widespread application of community water fluoridation as a 
method for preventing tooth decay. 

Fluoridation progress has been satisfactory in the large cities, 
but only 5fo of the almost 15,000 communities with populations under 
2,500 have fluoridated their water supplies. Since individuals having 
the necessary technical skills to plan and implement fluoridation often 
are not available in small communities. State health departments and 
the Division must provide substantial assistance to such communities in 
their efforts to obtain fluoridation. Although some progress has been 
made, the bigger job is yet to be done. 

Progress is being made in extending the benefits of fluoridation 
to people served by community water supplies, but more than one-third of 
the population of the United States consimies water obtained from other 
than commional sources. To meet this special need, simple and apparently 
practical methods for individual home water fluoridation have been 
developed and subjected to limited field testing. Attempts to stimulate 
private enterprise in making home fluoridation available to the general 



- 19 - 
population are being continued; however, conanercial concerns which might 
be expected to offer home fluoridation service are reluctant to do so 
until additional evidence is provided supporting the contention that 
home fluoridation is technically and economically feasible. 

In addition to providing assistance concerning fluoridation, 
Division staff will be working out of eight regional offices and the 
central office in I960, providing consultation and technical assistance 
in such areas as program and clinical administration, dental hygiene, 
informational materials development, and statistics. Division personnel 
engage in many cooperative activities with State health agency personnel 
helping them to identify the problems within the State which should 
receive primary attention, aiding in planning disease prevention and 
dental care programs, and assisting in program evaluation. Such 
consultation has proven invalioable in development of more effective 
State and community-wide programs. 
Training 

Assistance is currently being provided in a number of areas 
related to training. These include, among others, assistance to 
academic institxitions in developing curricula for dental health workers 
where Division staff members frequently serve as guest lecturers. 
Short courses on fluoride analytical methods are also provided for 
water works personnel. Also, within the Public Health Seirvice, the 
possible retirement of key career employees and added responsibilities 



- 20 - 
in the "broadening field of dental health have amplified the need for 
an expanded and accelerated program of staff training to Include 
graduate training in public health as well as assignment to regional 
offices and to State health departments to acquire programing experi- 
ence at those levels. 

DENTAL RESOURCES 

The activities of the Division of Dental Resources center around 
the search for more effective means of extending better dental care to a 
greater segment of the national population. The search for solutions 
today must be conducted against a background of manpower shortage, for 
the Nation's supply of active dentists has been declining relative to 
population for more than a generation. Our schools are still not 
producing enough new dentists to pace population growth even though 
enrollments have nearly doubled since the end of World War II. 

A reservoir of professional skills, more efficiently used, con- 
tinues, therefore, to be a first objective of the Division's program. 
During the past year, the Division of Dental Resources added another to 
its series of regional manpower studies which are designed to assist 
State and regional groups in planning for needed school expansion. 
After an appeal from the University of Illinois for assistance in 
determining that State's dental school expansion needs, the Division 
selected the Great Lakes region as the fourth to be surveyed. 



- 21 - 

The three earlier studies covering the West, the South, and more 
recently. New England, were completed in cooperation with the several 
regional boards of education. Consultative services and staff assistance 
continues to be provided to these regional organizations as well as to 
several universities in their efforts to enlarge dental training capacity. 
The Division plans during the coming year to complete the series of 
regional manpower studies with svurveys of the Midwest and Mid-Atlantic 
States and then to s\:iminarize and combine the completed series into a 
single publication defining the situation in the United States as a whole. 

Programs aimed at better utilization of the dentists' time and 
skills also continued in 1959* A research and demonstration project 
designed to teach dental students to use dental assistants effectively 
is now in its third year of operation. Six schools are participating 
and each has completed at least two years of the program. Since nearly 
all of the Nation's dental schools recognize the need to modify the 
dental school curriculum to assure that their graduates are versed in 
the technics of employing the assistant's skills productively, the new 
teaching methods being developed in this project will, when sufficiently 
evolved, have immediate and widespread application. 

Unless the use of chairside assistants can produce an increase in 
dentists' productivity comparable to that achieved during the past two 
decades by the wider employment of laboratory technicians, the shortage 
of dentists will grow considerably more serious. In the face of our 



- 22 - 
failxire to produce enough dentists to keep up with population growth, 
per capita demands for dental care are rising steadily~the product of 
a "better-educated, more health-conscious population. Dental care plans 
akin to Blue Cross and Blue Shield in the medical and hospital field are 
an important manifestation of this trend, and efforts to assure their 
orderly growth and measiire their impact will continue in I96O as an 
important activity of the Division. 

At the present time, three State dental societies have fully- 
operating dental service corporations, three others have completed 
incorporation of their service plans and will soon begin operation, and 
at least 10 additional State dental societies have plans in various 
stages of study or development. Fully-operating postpayment or budget 
payment plans now exist in 38 States. In addition to supplying the 
assistance requested during the past year by State societies, the 
Division cooperated with two States in studies of their postpayment 
plans. Also xinder study during the year were k different types of pre- 
payment plans serving specific popiilation groups. A part of the 
Division's continuing program is to develop and make available informa- 
tion which will help voluntary prepayment programs to be established on 
a sound basis. An analysis of utilization patterns in a health clinic . 
operated by a union was completed during the year, providing much needed 



- 23 - 
information on dental needs and treatment demands among a relatively 
low-income group. A similar study of dental seirvices given Public 
Health Service and Coast Guard families provided similar data for a 
better-educated, higher income group. 

SIM^RY 

In summary, programing for I96O has led to a shift in emphasis 
to studies most promising to the realization of the objectives of 
improving the oral health status of the Nation. Such programing at 
National Institute of Dental Research, while enabling a beneficial 
review of current programs, will further serve to prepare the Institute 
for the transition period related to occupancy of the new dental research 
building in November I96O.. During I96O, activity in the areas of dental 
public health and dental resources will be carried on at present levels 
of operation. Current programs in these areas will continue toward 
developing means for improving the potential of our limited dental man- 
power through use of auxiliary dental personnel; identifying oral 
disease problems on a national basis, and developing public health 
meas\ires such as fluoridation for use by those State and local authori- 
ties desiring progressive dental health programs. 

In the extramural programs of National Institute of Dental 
Research, grant awards will continue in I96O at essentially the same 
level with emphasis in the fields of oral systemic and chronic disease 
relationships, epidemiology, periodontal disease, and aging. Increased 
interest in the dental training program is indicated in the coming year. 



- 24 - 
In conclusion, it can be said that I96O is the year in which 
Dental Health activities will be primarily concerned with reviewing 
its ongoing programs pointing toward expansion into the most promising 
areas of basic and applied research in ensuing years. 



^^4i 



-f^^<--^ 



'^^^mrm 






^ 



J 



SUMMARY OF OPENING STATEMENT ^'-^^ 

by 
Director, National Institute of Arthritis and Metabolic Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

■'Arthritis and Metabolic Disease Activities" 



Mr. Chairman and Members of the Committee: 

The 19^0 budget request for Arthritis and Metabolic Disease 
Activities which is before you is for $31,215,000, which is the same 
as the amo\mt appropriated for 1959, but $57,000 greater than the 1959 
obligation plan. 

The past year has been a particularly significant one, with 
important advances in almost all areas of the Institute's responsi- 
bility. The newer programs are developing rapidly and, we believe, 
soundly. 

A great many examples of research progress could be cited. Of 
particular interest, perhaps, are: The development at Bethesda of a 
new synthetic pain- killing drug more powerful than morphine; the 
clinical testing of promising new drugs for rheumatoid arthritis 
and gout and progress in our understanding of these and related 
diseases; observations on oral drugs for diabetes including some new, 
more powerful compounds; further progress in the elucidation of the 
mode of action and the evaluation of these oral drugs; further 
progress in the development of a test for predicting the future 
appearance of diabetes; and a series of achievements in basic 



- 2 - 
research, notably in the biosynthesis and the elucidation of the 
metabolic role of the nucleic acids and in the detennination of the 
precise mechanisms involved in the protection of the body against 
blood loss. 

It is timely to report also that the international aspects of 
our programs are developing steadily and significant advances are 
being made in our collaborative studies in Peru on bums and bum- 
shock, our collaborative work on nutrition throughout the world, our 
new programs in geographic disease studies, and our sponsorship and 
participation in many important international conferences and 
symposia. 

Programs are developing satisfactorily in gastroenterology, 
including peptic ulcer, ulcerative colitis and ileitis, in cystic 
fibrosis and in physical biology. 



» 



^^^ ''-^r/ 



■««* M'Wi^T&f 






OPEWING STATEi'ffiWT "•"' ^lf:if 

by 
Director^ National Institute of Arthritis and Metabolic Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"National Institute of Arthritis and Metabolic Diseases" 



Mr. Chairman and Members of the Committee: 

The past year has been a particularly productive and rewarding 
one, and thanks to the support of this Committee new activities have 
been initiated in new fields and old which hold great promise for the 
future. In our older programs, examples of outstanding accomplishments 
are: The development of a new pain -killing dmig which has advantages 
over any hitherto available; further advances in the treatment and 
understanding of rheumatoid arthritis and related diseases; progress 
in the testing of tolbutamide and other newer oral drugs for diabetes 
and in clarification of their mode of action; and additions to our store 
of fundamental knowledge in such important areas of metabolic research 
as the clotting of blood and the biochemistry of nucleic acids, the 
chemical substances responsible for the transmission of hereditary 
characteristics. In addition, the programs in gastroenterology and 
physical biology are expanding rapidly and soundly, and a beginning 
has been made on the laxmching of a broadened attack on the important 
disease of children, cystic fibrosis. 



- 2 - 

The budgetary request before you is for $31^215,000 which is the 
same amount as was appropriated for 1959^ T^^'t $57,000 greater than the 
1959 obligation plan. 

NEW ANALGESIC 

One of the most significant and striking accomplishments of the 
year is the development of a new synthetic pain-killing drug which 
appears to be superior to any natural or synthetic compound hitherto 
available . 

This new analgesic, even though its synthesis in large quantities 
presents some difficulties, gives promise of making this country free 
of its present dependence on morphine -producing areas of the world. This 
scientific discovery is particularly timely, coming as it does at a 
period of imminent morphine shortage. 

Powerful pain-killing action, combined with much less tendency 
to addiction than morphine, has been the aim for many years of chemists 
engaged in the synthesis of analgesic drugs. This long sought goal 
now may have been achieved by Drs. Everette May and Nathan Eddy of 
the Section on Analgesics in our laboratories at Bethesda. A new com- 
pound, identified as NIH-7519, has been produced which is ten to 
twenty times more powerful than morphine yet on the basis of prelimi- 
nary laboratory tests appears to be less addicting than morphine. The 



- 3 - 
new drug, obtained by synthesis from simple coal-tar derivatives, not 
only is a powerf\il pain-killer but also has low toxicity, less 
depression of respiration, and gives excellent resiilts against certain 
forms of severe pain (deep root pain) which even morphine does not 
satisfactorily suppress . 

For many years chemists have been attempting to separate 
analgesic action from the addiction liability which long seemed in- 
herent in substances as potent as morphine. A wide variety of drugs 
have been produced, but generally the greater the pain-killing 
power, the greater also have been addiction and other harmful effects. 
NIH-7519^ however, gives preliminary promise that a partial separation 
of the analgesic and addicting properties may have been achieved. 

In bringing the information on this new analgesic to the 
fairly complete state reached at this time, several collaborative 
studies had to be arranged. Addiction studies in monkeys were con- 
ducted at the University of Michigan. Chronic toxicity studies 
and production of supplies necessary for clinical research are being 
carried on by Smith, Kline and French Laboratories. Patent appli- 
cations for assignment to the U. S. Government have been filed by 
our scientists. 



- 4„- 

RHEUMATIC DISEASES 
The year I958 marks the tenth anniversary of the discovery of 
the effectiveness of cortisone in the treatment of rheijmatoid arthritis. 
During this past decade there have "been very extensive efforts on the 
part of the pharmaceutical industry to develop new modifications of 
cortisone which would he more potent and, in particular, would be 
effective on long- continued administration with a minimiAm of serious 
side-effects. Four years ago, I had the privilege of reporting to this 
Committee that improved drugs, prednisone and the closely related 
prednisolone, had been synthesized by a pharmaceutical company and 
tested by National Institute of Arthritis and Metabolic Diseases Clinical 
Director, Dr. Bunim, in the Clinical Center at Bethesda, The advantages 
of these drugs over cortisone and hydrocortisone in most patients were 
striking and as a result they have replaced the earlier drugs to a large 
extent. During the past year, what appears to be another considerable 
advance has occurred. At the annual meeting of the American Rheumatism 
Association last spring. Dr. Bunim of Bethesda and Dr. Boland of 
Los Angeles reported the results of clinical trial of a new compound 
developed by two pharmaceutical companies, which is more active than 
prednisone and prednisolone and which appears to have a lower incidence 
of serious side-effects. In gouty arthritis (gout) another promising 
new drug has undergone extensive trial. 



- 5 - 

Further, the past yeax has witnessed great activity in the search 
for the cause of rheumatoid arthritis and related diseases. An area of 
particular activity has "been that of the possible relationship of hyper- 
sensitivity to the rheumatic diseases. An allergic component of rheumatic 
fever was postulated many years ago and a similar etiology might be 
suspected for lupus erythematosus and even for rheumatoid arthritis. Much 
new information along these lines has been accumulated during the past 
year but the evidence, although suggestive, is as yet inconclusive. It is 
still not at all clear whether by the immunologic approach we are on the 
verge of recognizing the cause of certain of the rhe^jmatic diseases or 
whether we are on a false trail. 

■ New attacks on the rheumatic disease problem also include a 
concerted drug evaluation program and the beginning of a program of 
genetic and epidemiological studies. Through collaboration with a local 
university, an outpatient clinic for rheumatic diseases has been estab- 
lished at D. C. General Hospital. Studies on large groups of patients 
in this clinic will supplement the intensive studies carried on in the 
Clinical Center at Bethesda. 
New, more effect ive antirhe umatic dru g. 

A new, more effective and probably safer steriod compound, 
dexamethasone, 25 times more potent than hydrocortisone and six 
times more potent than prednisone in the treatment of rheumatoid 
arthritis has been tested by Institute Clinicians and by others. 
A chemical cousin of cortisone, the new compound is the 



- 6 - 

latest result of the intensive efforts of pharmaceutical chemists to 
modify the basic cortisone molecule in order to increase antirheumatic 
effectiveness while decreasing the number and severity of undesirable 
side effects. Although not free of side effects, dexamethasone thus 
far appears to represent a definite advance over previous compounds. 

Institute clinicians, who also conducted the first clinical trials 
of prednisone in 195^^ reported on their preliminary tests with dexa- 
methasone last June, and have since confirmed that this new drug, as 
compared to prednisone at the same stage of testing, has produced fewer 
and milder side effects. At a recent conference on dexamethasone in 
New York City this same favorable impression was reported by other 
clinicians who are testing the new drug. Minor side effects noted include 
facial rounding and the stimiilation of appetite with resultant marked 
weight gain. Since arthritics often appear underweight, particixLarly 
during the first year of severe disease, this latter side effect may not 
always be undesirable. Although not completely eliminated, major side 
effects such as ulcers (common with prednisone), mental changes, hyper- 
tension, and interference with carbohydrate metabolism (steroid diabetes), 
seem greatly reduced in Incidence and extent on the basis of experience 
to date. Longer term trial, however, will be necessary to confirm these 
early findings. 



- 7 - 

Improved t^eatp^ent of gout . 

Studies of the metabolism of a drug used as a muscle relaxantant, 
coupled with the alert ohservation of an Institute grantee, have 
provided a potent drug for the treatment of gout which is now imder- 
going clinical trail by Institute clinical investigators. In promoting 
the rapid excretion of uric acid, it now appears to be three times more 
effective than any other drug now available. 

The drug itself, zoxazolamine (Flexin) is not new; it has been 
widely used for the relief of muscle spasm for several years. Its 
application to the treatment of gout followed the discovery that 
crystals appearing in the iirine of patients receiving the drug were uric 
acid. This observation gave the first clue to the muscle relaxant's 
powerful ability to promote the excretion of uric acid. 

The patient with gout through a probable metabolic shunt or 
short-cut, overproduces uric acid which accijmulates in the body. 
AccTjmulations of urate crystals form the characteristic tophi or 
deposioB corr^nonly found under the skin around joints and in ear lobes 
in patients with chronic gouty arthritis. One of the methods of dealing 
with the accumtjlation of excess uric acid is to increase its rate of 
exG.'.'c^oion, Zoxazolamine accomplishes this much more effectively than 
probenecid, the most active such drug now in use, on the basis of tests 
and trials to date. An added advantage over probenecid is that action 
of the new drug is not inhibited by aspirin, Zoxazolamine is thus far 
relatively non-toxic and not onJ.y in-ilbits the formation of tophi but 
seems to reduce the size of those already formed. 



- 8 - 

Studies OQ the cause of rheumatic diseases 

One of the major laboratory efforts to obtain basic understanding 
of the disease, rheimiatoid arthritis, is directed toward determining the 
precise nature of the substance known as the rheumatoid factor in the 
serum of patients with this disease. This particular substance, peculiar 
to patients with rheijmatoid arthritis, has already been made use of as 
a diagnostic label and is the substance detected by various diagnostic 
tests developed by our grantees and by our own laboratories. The newest 
and simplest of these tests developed at the National Institutes of 
Health was reported to this Committee last year. It is interesting to 
note that this test in its original form was developed for use in the 
detection of trichinosis, a disease of far different characteristics and 
totally unrelated to arthritis. 

This past year particular laboratory progress in this area has 
been made not with a diagnostic test but with characterization of the 
factor at its root. Institute scientists have developed a unique and 
accurate method for determining the relative activity of pTirified 
preparations of rheumatoid factor and for precisely measuring its quantity 
in the serum. This new method can detect in blood relative differences of 
activity much more sensitively than by any previous means and can provide 
reproducible quantitative values with extraordinarily fine accuracy. 
The new technique depends in part upon previous research in the virus 
diseases and is felt to have significance beyond the confines of 



- 9 - 
rheumatic diseases, the basic principle, that of combining a protein 
(in this case, the rheumatoid factor) \rith a second protein (in this 
case, a virus), affords a method of measuring the exact concentration 
of the first protein in a way which should be applicable to protein 
measurement in a wide variety of studies, indicating the diversity of 
application of sound basic research processes and methods. 

The rheumatoid factor thus far has been found to be a gamma 
globulin, a species of blood protein in which are found the antibodies 
or substances which provide the body a variable degree of immunity to 
particular diseases. This has increased the possibility to some extent 
that rheumatoid arthritis may have as its basis an unusual and dele- 
terious immune reaction to a foreign or an altered native substance, 
manifested by both generalized or constitutional disease and localized 
reaction in certain joints. Tbe immunological approach to solution of 
rheumatoid arthritis is being vigorously pursued by a large proportion 
of National Institute of Arthritis and Metabolic Diseases grantees, as 
evidenced by the scientific program of the recent Interim Session of 
the American Rheumatism Association. V7e are not convinced, however, 
that immunological studies are certain to produce the ultimate 
definition of this disease and are consequently pushing forward our 
support on as many fronts as appear logical and promising. 
P rogram developments 

A chain of arthritis clinics spanning the country 
is being organized in a cooperative venture to provide, for the 



- 10 - 
first time^ a strictly objective, precise and uniformly disciplined col- 
laborative evaluation of the therapeutic effectiveness of drugs employed 
in the treatment of rheumatoid arthritis. The American Rheumatism 
Association, of which Dr. Joseph J. Bunim, Institute Clinical Director, 
is president, in cooperation with and with the support of the Arthritis 
and Rheumatism Foundation and the National Institute of Arthritis and 
Metabolic Diseases, is setting up the combined clinic organization to 
accomplish this long-needed service. Continuing results of this program, 
expected to operate over the course of several years, will provide a 
source of thoroughly reliable information concerning the absolute and 
relative merits and limitations of the several antirheumatic agents now 
in use and to be developed in the future. 

Our intramural clinical investigations unit, recognizing the value 
of larger numbers of ambulatory patients in drug evaluation, has estab- 
lished in collaboration with Georgetown University and outpatient clinic 
in rheumatic diseases at D. C. General Hospital. This will enable us to 
complement detailed studies on small groups of patients in the Clinical 
Center with less intensive studies on larger groups of selected individuals 
with rheumatic diseases. 

There has recently been added to the clinical staff a well-trained 
epidemiologist. He will receive clinical training in rheumatology in the 
Clinical Center and field training in population studies of rheumatic 
diseases in England and vdll then be ready to undertake population studies 
in this country, 



- 11 - 

DIABETES 

Throughout the country a sustained surge of interest in diabetes 
research has occurred during the past three years. Two factors are 
primarily responsible- -the development of oral antidiabetic drugs and 
the increased grant support available from the Institute, 

The emergence of tolbutamide (Orinase) as an effective therapeutic 
agent for certain types of diabetes has had a stimulating effect upon all 
aspects of the situation. Patients for whom the drug is suitable have 
been provided with a much simpler method of control of their disease than 
insulin; the pharmaceutical industry is busily at work in attempts to 
develop similar yet better drugs, with some success, as will be described; 
physicians and scientists have been exhibiting more interest in diabetes 
problems, and more and more of them have been drawn actively into 
research in this field. In the Institute's own laboratories, work along 
lines related to diabetes problems has been expanded, particularly in the 
areas of metabolism, biochemistry and endocrinology fundamental to 
increased knowledge concerning the disease process itself, as well as 
in studies of the action of both the new drugs and insulin. Meanwhile, 
training programs, supported by grants from the Institute to medical 
institutions and individuals throughout the country, are providing an 
increasing supply of trained research scientists and physicians ever 
better prepared to attack and solve the highly involved problems this 
complex disease presents. 



- 12 - 
The oral antidiabetic drugs 

Insulin, since 1921; had been the one effective antidiabetic agent 
in general use throughout the vorld until the advent of the oral anti- 
diabetic drugs, carbutamide (BZ-55) and tolbutamide (Orinase). Beginning 
in 1955 these two drugs were thoroughly tested in this country, and one, 
tolbutamide, emerged successfully from the long series of clinical trials 
and was placed on the market in June 195?. Trials showed that BZ-55 ^as 
too toxic, and it was never released for general use. 

In October of 1958 another new oral antidiabetic drug, chlorpro- 
pamide, passed its trials and was made available to diabetics upon 
prescription from their doctors. This drug, sold as Diabinese, is a 
sulfonylurea like tolbutamide. It has been thoroughly tested, and is 
apparently relatively free of side effects, and being more potent can be 
given in smaller doses than tolbutamide; experience to date suggests that 
chlorpropamide exerts its effects over a longer period and so may provide 
smoother control of the blood sugar than tolbutamide. 

Still another new oral drug is now being tested and may be released 
in the near future. Known as metahexamide, it, too, is a sulfonylurea 
compound related to tolbutamide. Early indications are that it also may 
be more potent and have longer-lasting effects. 

Not new this year, but still being tested, is a compound, phenformin 
(DBI), which is not a sulfonylurea so that it acts in a different manner 
and is effective in some cases where the sulfonylureas are not. However, 
DBI has also been found to bring on distressing gastrointestinal side 
effects in some patients. 



- 13 - 

As the year 1958 ended^ it was reliably estimated that in this 
country more than i+00^000 diabetic patients were being maintained on 
one or another of the oral drugs. Thus^ almost one -third of the known 
diabetics in this country appear to have been transferred to oral 
medication from insulin injection. 
Clinical testing 

Institute scientists and grantees are collaborating with the 
Veterans Administration in the prosecution of a large-scale study of 
diabetics in veterans hospitals. In addition, increased support has 
been given clinical investigators in the medical schools of the country 
to determine, in large groups of patients and for long periods of time, 
the precise value of the new drugs in controlling diabetes and in pre- 
venting diabetic complications. Although it is, of course, far too early 
to have learned the value of the oral compounds in preventing the late 
complications, a great deal of progress has been made in determining their 
value in day by day control of the obvious manifestations of the disease. 

The sulfonylureas are effective only in those diabetics who 
contracted the disease during their later years. They are not effective 
in cases of severe or "brittle" diabetes in which the onset of the 
disease occurred in childhood or in the very early adult years — cases 
in which there is little or no ability of the beta cells to function in 
supplying the insulin normally needed by the body. With these limita- 
tions in mind, however, the oral drugs appear to be very effective in 
diabetes control. 



- lU . 

The oral antidiabetics certainly can be considered a major advance 
in the treatment of diabetes, freeing many patients of the onerous ne- 
cessity of using the hypodermic needle needed for insulin medication. 
It must be borne in mind, however, that the oral compounds now available 
do not themselves act as insulin does. It is not yet surely known Just 
how these drugs act, despite extensive research by many scientists. The 
weight of evidence to date has indicated that the sulfonylureas act to 
stimulate the beta cells of the pancreas to produce more insulin. In- 
creasing evidence has been accumulating during the past year, however, 
which stresses differences in their action from those of insulin, with 
significant effects upon the liver and upon peripheral tissues such as 
muscle, indicating that the blood sugar controlling action of these drugs 
is exceedingly complex. 
Small dose cortisone test for predicting future appearance of diabetes 

Two years ago we reported to this Committee that a National 
Institute of Arthritis and Metabolic Diseases grantee at the University 
of Michigan had suggested a method of determination of diabetes suscepti- 
bility. In families in which diabetes occurs, some members may be normal, 
some frankly diabetic, some show poor glucose tolerance although probably 
not diabetic, and a fourth group appear to be essentially normal in their 
responses to the glucose tolerance test unless they are given cortisone. 
Early studies had suggested that cortisone might tend to unmask a latent 
diabetes in those who have a family history of the disease but who show 



- 15 - 

no diabetic signs in ordinary tests. The grantee has now completed a 
screening in 5OO persons using the small-dose cortisone test he had 
suggested. The screening indicates that the test will provide an 
extremely reliable index of "pre -diabetes " . Of 259 apparently 
normal relatives of diabetics given the small dose cortisone test, 
one -fourth showed positive res\ilts. Follow-up of this latter group 
has revealed that lyjo have developed diabetes and an additional lO/o 
are classed as "probably" having diabetes; among negative reactors 
to the new test only 2fo have developed diabetes. A five-year followup 
is now planned from which final conclusions can be drawn. 
Effect of training grants 

Training grants are given not only in diabetes but also in 
arthritis, gastroenterology, metabo3ism, hematology, and physical 
biology. Their effectiveness in all of those fields can be illustrated 
by data for diabetes obtained by the American Diabetes Association. 

The first national conference on teaching and research in 
diabetes was sponsored by the American Diabetes Association and the 
National Institute of Arthritis and Metabolic Diseases and was held at 
Atlantic City on May 3, I958. 

The extremely important role of the National Institute of Arthritis 
and Metabolic Diseases' training programs in strengthening diabetes 
education and research was brought out in the results of a questionnaire 
circulated by the American Diabetes Association to medical schools prior 
to the conference. The questionnaire, to which 0^^$ responded, revealed 
that since 195^ an increase of 250^0 has occurred in the number of 
physicians receiving post-graduate clinical training in diabetes, 



- 16 - 
an.d an increase of 3OO/5 ^^ the number of post-doctorate diabetes research 
fellows. In the medical schools in 195^ diabetes training involved only 
two areas of medicine but in 1958 on the average involved eight areas of 
medicine. Seventy percent of the medical schools now give post-graduate 
medical courses in diabetes. 

METABOLISM 
As we have related to this Committee in past years, one of the 
strongest efforts of this Institute is placed in the support of basic 
research in the biochemical or metabolic processes by which the body 
carries out its great number of tasks. These studies involve definition 
of the enzymes which catalyze biochemical reactions, investigation of 
the actions of the hormones which in considerable measure are believed 
to exert their effects by regulating enzymatic processes, and study of 
nutritional and other influences on the means by which the body obtains 
energy for growth and work. An extremely important aspect of metabolism 
research in recent years has been the investigation of diseases for the 
possibility that a defect or absence of a key enzyme (a defect transmitted 
under genetic influence) may be responsible for the disordered processes 
found; a number of these so-called "molecular diseases" have been found 
by our laboratories, such as, galactosemia, alcaptonuria, and congenital 
non-hemolytic jaundice. The search for others is involving ever more 
difficult studies since it is becoming evident that the remaining diseases 
of this type have biochemical defects that are far less obvious. The 



- 1? -. 

biochemical lesions probably involve not total enzyme lacks but relative 
deficiencies, enzyme warping or distortion, or a failure to produce 
needed extra amounts of an enzyme when a stress situation demands. 

This aspect of metabolism places great importance upon the nucleic 
acids and nucleoproteins since they are at the heart of the processes by 
which cells and tissues genetically transmit from one generation to the 
next the capacity to produce distinctive and vital proteins, such as 
enzjrmes, hormones and antibodies. Grantees and intramural investigators 
of the Institute are continuing important studies of the structure and 
mode of synthesis of nucleic acids. 

Noted below are a few significant examples of developments in 
basic studies of metabolism. 

Biochemical step found which helps explain why man cannot synthesize 
Vitamin C 

An unusual characteristic shared by man, monkey and guinea pig is 
the inability to make within their own bodies ascorbic acid, or Vitamin C, 
essential for the maintenance of connective tissue, bone, and teeth. 
Consequently, unlike other animals, man, monkey and guinea pig must 
obtain Vitamin C from food. Recently biochemists from the National 
Heart Institute and the National Institute of Arthritis and Metabolic 
Diseases for the first time Isolated an intermediate breakdown product 
of glucose metabolism which plays a key role in the synthesis of Vitamin C 
in those animals able to do bo and thus ^frere able to point more closely 



- 18 - 
to the defect in Vitamin C metabolism in man. In other mammals, a sugar, 
L-gulonic acid, is converted to ascorbic acid and xylulose, a five-carbon 
sugar or pentose; it was an intermediate in this conversion that was 
found and described for the first time. In man, however, only xylulose is 
formed, never any Vitamin C. Occasionally a companion defect is also 
found in man whereby xylulose is not metabolized properly, accumulates 
and spills over into the urine to cause the condition known as pentosuria. 
This condition is not believed to be of serious clinical importance but 
pentose in the urine is occasionally mistaken for glucose and an incorrect 
diagnosis of diabetes made. Thus, these basic carbohydrate studies shed 
light both on the Important nutritional element. Vitamin C, and on the 
unusual disorder known as pentosuria. 
Action of fibrinogen and thrombin in blood clotting revealed 

Scientists in the Institute's laboratories have recently increased 
our understanding of how an important step in the blood clotting process 
actually works to halt the flow of blood. They have found, first of all, 
that thrombin is essentially a protein-splitting enzyme, very similar in 
structure to other proteolytic enzymes like trypsin which have long been 
well known for such action in other parts of the body. In the process of 
blood clotting, the enzyme thrombin has been found to attack the protein 
fibrinogen and to chop off two segments known as peptide chains. Physical 
chemical studies have indicated that these two peptide chains have 
negative electrical charges so that in place on the fibrinogen molecule 



m 



- 19 - 
they help to repel neighboring fibrinogen molecules; once these chains 
have been cut off, however, when clotting is needed, the repellent action 
is eliminated and the remaining portions known as fibrin molecules clump 
together in the rubber-like mass of a clot. Even more recently, however, 
it has been determined that one of the severed peptide chains has a drug- 
like action which causes the ends of severed blood vessels to constrict, 
an effect which would aid in the firm fixation of a fibrin clot. In this 
portion of the complex process of blood coagulation alone, three different 
kinds of action have thus far been demonstrated, enzymatic, physico- 
chemical, and pharmacological, Indicating the variety of techniques and 
talents required in any modern research project, even in one of relatively 
limited scope. 
Nucleic acids 

One of the most rewarding fields of basic research today appears 
to be that of the nucleic acids. Research progress has been made in the 
past year both by Institute investigators and by grantees. The major 
areas of progress have been in elucidation of structure, in the biosynthe- 
sis of these compounds and in the determination of their physiological 
role, particularly in the transmission of hereditary characteristics. 

It is believed to be the nucleic acids and in particular 
deoxyribonucleic acid (DNA) which controls the development of complex 
organisms from the fertilized egg- -the differentiation of cells into 
organs and the developments of species and Individual characteristics, 



- 20 - 
thus providing for hereditary continuity. It is believed to be through 
defects in these nucleic acids that hereditary or familial diseases are 
transmitted--cystic fibrosis, galactosemia, susceptibility to diabetes 
and many others. 

Employing bacteria and other simple organisms, investigators have 
shown that viruses may lie dormant through many generations, then either 
spontaneously or because of some external factor erupt into disease; and 
that viruses may carry genetic material from one host to another. 
Investigators have also made extensive progress in "mapping" of genes 
composed largely of DM, i.e., in establishing which portions of the 
chromosome controls specific characteristics of the developing organism 
and in determining the nature of the abnormal chemical changes in the 
nucleic acids which result in hereditary defects. 

These studies cannot be related to any given disease in man; in 
fact, predictions cannot be made as to which particular area this type 
of information will prove most important. Nevertheless, it can be 
stated with some assurance that the information derived from these studies 
will affect profoundly the whole future course of biological and 
categorical research. 

PHYSICAL BI0L0C3Y 

The National Institute of Arthritis and Metabolic Diseases is 
charged with the responsibility for developing the field of physical 
biology, that important research area which utilizes the principles and 
methods of the physicist in studies in biology. This responsibility 



- 21 - 
has been discharged during the past year through notable increases in 
research grants and training grants and by additions to our intramural 
staff. At present there are Qk active research grants in physical 
biology. Nine training grants of considerable size have been avrarded. 
Despite the relative newness of this area of activity, notable research 
progress has been made in such fields as the physical chemical behavior 
of macromolecules, energy reception and transfer in photosynthesis, 
coding and information theory, and the biological effects of radiation. 
Three examples follow. 
Nature of molecular bonds studied by new physical biology techniques 

The molecules of all proteins and of many other substances are 
held together by hydrogen bonds, many of which are forming and breaking 
thousands of times a second. Recent studies with new techniques indicate 
that large molecules are not always held together in straight lines but 
sometimes in a cyclical arrangement. This unusual finding in fine, 
molecular structure research has been made possible by an advanced 
electronic technique known as nuclear magnetic resonance. This technique 
involves placing the test substance in a strong and very stable magnetic 
field and bombarding it with radio waves j from the varying absorption 
of radio frequencies can be told the kinds of atomic particles present 
and precisely where they are located. An exact knowledge of molecular 
arrangements and bond shapes is of vital importance to scientists inter- 
ested in the structure of such important large molecules as the nucleic 
acids and the proteins, for example, insulin and fibrin. 



- 22 - 
Mathematical analysis speeds blood coagulation research 

Studies of the blood coagulation process have recently pointed up 
the important contribution that advanced mathematics can make to the 
field of biochemistry. A biochemist-hematologist and a bio-mathematician 
have analyzed the reactions leading to the formation of two intermediates 
which appear when prothrombin is converted to thrombin, the enzyme which 
must be present in the blood before clotting can take place. Following 
up on previous work by the biochemist which had demonstrated the presence 
of an inhibitor of blood clotting in human plasma, the two men applied a 
combination of both experimental and mathematical analysis in which the 
mathematics not only proved the validity of the "working hypothesis" 
drawn from laboratory investigation, but provided additional conclusions 
which were later confirmed experimentally. It was shown, as a result, 
that the clotting inhibitor binds a product which is intermediate between 
prothrombin and thrombin, the amount of binding depending upon the rate 
of the prothrombin-to-thrombin reaction. Such a rate dependence tends 
to prevent slow clotting within blood vessels which might lead to 
dangerous thrombosis, but does not interfere with the rapid clotting 
necessary to stop hemorrhage from an injured blood vessel. The very 
complex problems of biological research today make the application of 
higher mathematics more and more important and necessary, for the 
research hypothesis often is removed from its experimental results by a 
long chain of deductions so that only by formalized mathematical 
analysis can the proper interpretation of results be made. 



- 23 - 
New instrument measures breathing resistance 

Physical biologists in Institute laboratories have developed a 
nev device for measuring airway resistance to normal and abnormal respir- 
ation and for determining air pressure within the lungs. The instrument, 
known as a whole body plethysmography has revealed some striking 
information concerning respiration. Employing the new research tool the 
scientists found that oxygen uptake from the lungs into the blood stream 
is a continuous process, one that goes on even while the lungs are 
motionless during breath -holding. With the plethysmograph they have 
also shown that each heart beat creates a negative pressure which brings 
air into the lungs, an event masked by normal respiration. Neither of 
these processes had been visualized previously. The new instrument 
initially will supply more basic information about the physiology of 
respiration; later it may find clinical use in evaluating therapy for 
asthma and other conditions involving increased lung airway resistance. 

GASTROENTEROLOGY 

In recognition of the importance of the gastrointestinal dis- 
orders, including peptic ulcer, ulcerative colitis and regional ileitis, 
the National Institute of Arthritis and Metabolic Diseases has 
intensified its efforts in the support of basic and practical problems 
in this area. 

Both research and training have been fully supported through the 
grant mechanism. At the present time there are 155 active research 



- 2k - 
grants in this area and 25 training grants have been awarded. As a 
result of the interest and support of this Committee and the active 
steps which have been taken by members of our staff and workers 
interested in the field, much more research and training activities are 
in progress than at any previous time. This accelerated activity is 
beginning to produce results as evidenced by recent progress in our 
understanding of the malabsorption syndrome and in other areas. A 
modest beginning has been made toward our intramural research program 
in gastroenterology. 
Progress in ulcerative colitis 

Early last year under the joint sponsorship of the National 
Institute of Arthritis and Metabolic Diseases and the General Medicine 
Study Section, seventy basic and clinical investigators from various 
U.S. medical centers met to dissect and examine the disease problem, 
ulcerative colitis. The conference, entitled "New Frontiers in 
Ulcerative Colitis" heard reports from nine senior research workers 
and resulted in evident stimulation of research interest. The most 
valuable discussion centered around l) review of the tremendous variety 
of etiologic agents and mechanisms which have been suggested (infectious, 
neurogenic, and immunologic most frequently) without conclusive evidence 
for any; 2) the search for an experimental disease counterpart in 
animals; 3) the explosive advance in our knowledge of the viruses which 
inhabit the intestines (enteroviruses) in conjunction with which study 



- 25 - 

of their possible relationship to ulcerative colitis has just been 
initiated; and h) the delineation of distinctive biologic and psychologic 
features in the ulcerative colitis patients which suggests a charac- 
teristic personality structure and in turn the possibility of an inborn 
error of metabolism under genetic control as one necessary factor for 
susceptibility, other undetermined factors also being needed to develop 
the disease. 
World Congress of Gastroenterology 

Nearly 2,000 clinicians and investigators from 50 countries 
attended the World Congress on Gastroenterology held in Washington 
May 23-31^ 1958« Host organization vas the American Gastroenterological 
Association, whose president. Dr. Clifford J. Barborka, has been so 
instrumental in arousing interest in the problems surrounding this 
specialty. The meeting, substantially supported by a grant from the 
Institute, was most successful in providing those attending with worth- 
while information, challenging concepts, and stimulating ideas. It also 
served to focus public attention upon gastroenterology. 
Malabsorption; gluten-free diet for the treatment of non- tropical sprue 

Relief from the disagreeable and deleterious symptoms of non- 
tropical sprue has been brought this past year to many sufferers from 
this important gastrointestinal disease. This valuable therapeutic 
success was achieved by National Institute of Arthritis and Metabolic 
Diseases grantees who have devised an effective diet which is essentially 



- 26 - 
free of wheat, rye, and oats. Non-tropical sprue is probably the 
largest entity in the group of diseases known as malabsorption syndrome 
and is characterized by a long-lasting debilitating diarrhea, weakness, 
weight loss, and many other signs resulting from failure to properly 
absorb important nutritional substances. Working from earlier reports 
that gluten, one of the major fractions of cereal grains, might be the 
offending agent, the investigators first did metabolic balance studies 
on sprue patients and found that elimination of gluten from the diet 
increased absorption of fat and important minerals, and penaitted 
replenishment of body protein stores. Clinical trials were then 
employed and resulted in such a high rate of success that a gluten-free 
diet is now confidently recommended for the treatment of non-tropical 
sprue . 

CYSTIC FIBROSIS 
It is estimated that perhaps as high a proportion as 1 in 1,000 
children born in this country develop the serious familial disease, 
cystic fibrosis. In recognition of the gravity of this situation, the 
Congress last year directed that a determined effort be made to plan a 
research attack upon the fundamentals of this disease, perhaps beginning 
with a scientific conference of the type which has proved so effective in 
other fields. The metabolic aspects of the research attack were entrusted 
to the National Institute of Arthritis and Metabolic Diseases, the in- 
fectious aspects to the National Institute of Allergy and Infectious 
Diseases, 



\ 



- 27 - 

The two Institutes, in collaboration with the National Cystic 
Fibrosis Research Foundation arranged for a three-day conference of some 
sixty research workers representing not only present interest in clinical 
and basic aspects of cystic fibrosis but representing also ancillary 
interests such as endocrinology, biochemistry, physiology, etc. This 
conference took place January J, 8 and 9, 1959; and was eminently 
successful, Our present knowledge of the metabolic and infectious 
aspects of the disease was summarized and possible new approaches to an 
increased understanding of the basic defects underlying the disease 
were outlined and discussed. 

As a further step in the accelerated attack upon this disease, 
we have undertaken the recruitment of a pediatrician with a very high 
degree of clinical competence and a special interest in cystic fibrosis 
in order to make available to him as the leader of an intramural research 
team, our unique facilities at Bethesda. We believe that our search for 
such an individual has been successful, although the formal announcement 
of his appointment could not be made at the time of writing. 

In addition, progress has been made in mounting a nation-wide 
attack on this disease as evidenced by increased requests for research 
and training support. It must be stated, however, that the effects of 
the increased availability of funds, of the conference, and of the 
concerted endeavors of the National Institutes of Health staff and of 
interested individuals throughout the country to stimulate increased 



- 28 - 
research efforts are just beginning to "be felt. In the months and years 
ahead, ve can confidently anticipate an accelerating effect from the 
impetus which has so recently been applied. 

It is, of ccurse, too early to report a great deal in the way 
of research accomplishments from our increased efforts. As a result of 
studies underway for some time, however, progress in our understanding 
of cystic fibrosis is being made. It can now be said that at least for 
mild cases with early diagnosis, the disease will not of necessity 
terminate fatally in early childhood. 

We have also learned, as the result of studies which have been in 
progress, much more of the general nature of the disease; we know that 
v;e are dealing with a disorder which may affect all of the glandular, 
epithelial structures which have been studied -- the bronchial tubes of 
the lungs, the pancreas, the gastro-intestinal tract, the sweat glands, 
and even the tear glands. An important fact with regard to the genetic 
aspect of cystic fibrosis has evolved from the diagnostic test of sweat 
chloride in that with this test we can now recognize individuals who do 
not have the disease but are capable of transmitting it to the next 
generation. Finally, this past year a significant piece of fundamental 
information has been uncovered. The mucopolysaccharides of the intestines 
contain among other substances two unusual sugars, fucose and sialic 
acid. The ratio of these two sugars in a polysaccharide seems to 
determine its solubility. In the intestinal mucus from patients with 



- 29 - 
cystic fibrosis has been found a highly insoluble polysaccharide, poor in 
sialic acid and rich in fucose, a physicochemical finding which might 
account for the tenacious nature of these secretions in cystic fibrosis 
patients. This discovery may be the first really important advance 
toward understanding the basic defect in the tissues of patients with 
this disease. 

It is obvious that much remains to be accomplished. All of those 
interested are hopeful that the augmented attack on the disease will 
bear early fruit. 

IMPORTANCE OF A BROAD RESEARCH ATTACK 

Throughout the foregoing account of the activities and accomplish- 
ments carried on and supported by the National Institute of Arthritis 
and Metabolic Diseases may be detected instances where effective research 
in one field was made possible by advances and discoveries in another 
field, thus suggesting the value of avoiding too constricted an approach 
to the conquest of a partic\ilar disease. The importance of stimulating 
and supporting research along many fronts seems best illustrated by some 
important break-throughs made possible by arduous efforts to advance 
broad fundamental knowledge. Most often these were basic studies in 
which at their inception and during the course of their development the 
investigators had no thought that their results would soon be useful in 
clinical disease, often a disease in a field quite distant from that of 



- 30 - 
the basic research. Occasionally progress in one field has stemmed from 
a successful therapy in another field which carried an unwanted but 
provacative side effect. 
Treatment of typhoid fever "-"discovery of the oral drugs for diabetes ; 

In February 1957^ a conference was held at the New York Academy 
of Sciences at which 33 scientific papers were presented siommarizing 
the knowledge to that time of the clinical effects and mechanism of 
action of the oral drugs then known for diabetes. What circumstances led 
to the discovery of these drugs? Dr. Rachmiel Levine, distinguished 
carbohydrate chemist and physiologist, introduced the conference with 
the following words: "The present conference is a consequence of 
deliberate and well-planned research based upon a series of chance 
observations in a field far removed from diabetes. But for M. Janbon's 
fortuitous observation that one of the newer sulfonamides of 19^2 
produced a disorder very similar to hypoglycemia, August Loubantieres 
very probably would not have devoted the next fifteen years to an effort 
to ascertain the nature of these symptoms and to analyze the mechanism 
which produced them. The sulfonylureas were originally designed as more 
soluble sulfa drugs with prolonged action, and their effects in diabetes 
were consequences of unexpected activity." 

The investigator who first noted the blood sugar lowering effect 
which was to lead to these important drugs for the treatment of diabetes 
was working in an infectious disease clinic in a medical school in France. 



- 31 - 
He was studying the therapeutic effect of a new derivative of sulfanila" 
mide in patients with typhoid fever. He noted that this drug produced 
in some patients symptoms and signs resembling hypoglycemia. The chemical 
data revealed low values for blood sugar, and intravenous injection of 
glucose was helpful in alleviating the symptoms in some patients. This 
unexpected circumstance was described to a colleague, Loubatieres, who 
had a long experience in experimental diabetes, and he set to work on 
the action of that sulfonamide, known as 225^-RP. From these studies 
eventually came in 1955 the first widely tested blood sugar lowering 
sulfonamide, BZ-55^ and thence the present furious research activity on 
a variety of important antidiabetic compounds. Efforts directed at the 
chemical synthesis of a more effective antibiotic yielded a compound 
with a deleterious side effect which was then turned to useful effect in 
an entirely different disease. 

Basic endocrinology treatment of rheumatic diseases 

This year marks the tenth anniversary of the first administration 
of a synthetic adrenal hormone, cortisone - with astounding success - to 
a patient with severe rheumatoid arthritis. This remarkable event would 
not have been possible without the painstaking efforts of a chemist, 
Edward C. Kendall at the Mayo Foundation, to work out the various complex 
steps by which, starting with the cholesterol ring structure, certain 
hormones could be fabricated in the laboratory. This effort required 
several years and was originally inspired not from a planned effort to 



I 



- 32 - 
deal therapeutically with rhexmiatic diseases but from the realization 
that the adrenal cortex was able to make several hormonal substances 
which exerted delicate control of certain important body processes; 
the most evident of these processes was regulation of the excretion or 
preservation of the body's stores of salt and water. 

These complex hormones are made in the body in such tiny amounts 
that study of their effects, of their manner of metabolic regulation, 
was seriously hampered. The only hope for obtaining them in sufficient 
quantity for successful study of their actions and function lay in 
synthesis in the laboratory, and this Kendall set out to do. Meanwhile 
the clinician. Dr. Philip Hench, was watching this work in basic 
endocrinology with interest. It had occurred to him, as it had to 
others, that some chemical regulator or hormone might yield a beneficial 
influence in rheumatoid arthritis; this thought was based on the clinical 
observation that during jaundice and pregnancy the painful and crippling 
aspects of arthritis abate. In jaundice and pregnancy some subtle 
changes in hormonal balance must occur, changes which even now are not 
yet defined. Finally in 19^8, when Kendall had completed his laboratory 
synthesis of Compound E or cortisone, planned as a method for obtaining 
a better way of studying hormone action, Hench was able to take a 
small amount for administration to a patient with arthritis and with the 
gratifying results now so well known. 



- 33 - 

Altiiuut^ the principal result of this utilization of endocrine 
research in rheumatology has been great relief of suffering in patients, 
important by-products have been the stimulation of much greater research 
in both endocrinology and rheumatic diseases. Particularly, studies 
have been pushed on the function of many other hormones and of the 
influence of hormones on various processes thought involved to varying 
degrees in rheumatic disease - on the synthesis and metabolism of 
collagen of connective tissue, on antibody production and on inflammatory 
response to traumatic, bacterial, chemical and hypersensitive stimuli, 
all as influenced by hormonal action. 

Metabolic studies of adrenal insufficiency"--diagnostic test for cystic 
fibrosis 

Although a large number of investigators and alert physicians, 
beginning with Thomas Addison in l855^ have contributed a variety of 
important bits of information which have led to our present extensive 
knowledge of the adrenal glands, it was Loeb and Harrop in 1933 at 
Columbia University Medical Center who demonstrated that patients with 
Addison's disease (adrenal insufficiency) and adrenalectomized dogs lose 
large quantities of sodium and chloride in the urine. Columbia has 
since been an important center for the study of adrenal disease, and the 
symptoms and signs of adrenal insufficiency have been particularly fa- 
miliar to members of its medical staff. It is not difficult to 
understand, then, that when babies and children with the disease, cystic 



- 3^ - 
fibrosis or fibrocystic disease of the pancreas,, were often brought to 
Columbia's Babies Hospital during a very hot summer in a state of 
collapse, it occurred to a young physician, di Sant'Agnese, that they 
appeared like patients with Addison's disease who had lost great 
quantities of salt and water. Being familiar with the tests for the 
adrenal disease, di Sant'Agnese tested the blood and found it low in 
sodium and chloride in these seriously ill young patients. Unlike 
Addison's disease, however, the route of excessive salt loss was found 
not to be by way of the kidneys but by way of the sweat glands. Further 
study of sweat chloride and sodium in a variety of diseases revealed 
that only in cystic fibrosis was there an abnormally great excretion of 
salt in the sweat. Thus was devised the specific and now widely used 
diagnostic test for cystic fibrosis. 

Rheumatic disease--endocrine studies of mucopolysaccharides — adjunct to 
the therapy of galactosemia 

Within the past year investigators in our Institute laboratories 
have been studying the effects of endocrine hormones upon various 
tissues and metabolites important in rheumatic disease; they have noted 
that certain hormones play an essential role in the metabolism of joint 
tissues studied in the test tube and of certain sugars essential to the 
structure of mucopolysaccharides in connective tissue. One of these 
sugars, fucose, it was realized, is structurally closely related to 



- 35 - 

galactose, the milk sugar which is inadequately metabolized or used for 
energy by a child with galactosemia. It was decided, therefore, to 
subject galactose to similar studies of hormonal influence. 

By detailed metabolism experiments involving labeling the sugar 
with radioactive carbon and measiiring the radioactive carbon dioxide 
released when hormones are added, it was found that three hormones 
greatly increased the metabolism of galactose; it was further determined 
that this increase in metabolism does not occur through stimulation of 
the action of any of the known enzymes or protein catalysts in the known 
galactose metabolism pathway, strongly suggesting that a new and differ- 
ent pathway for utilizing galactose must exist upon which the hormones 
exert their stimulation. 

The studies now shifted from the discipline of biochemistry to 
that of physiology, the study of function, with particiiLar emphasis on 
the hormone progesterone, since of the hormones active on this process 
it alone is virtually free of harmfiil side effects. First the scientists 
were able to show in rats that the formation of galactose cataracts 
could be retarded by progesterone; rats fed excessive quantities of 
galactose develop cataracts of the eye just as do patients who have the 
natural disease. Finally, one of the investigators being a clinician, 
turned to the study of a galactosemic patient and demonstrated that 
administration of progesterone would bring about metabolism of galactose. 
Further studies are planned to determine more definitively the place of 
progesterone as an adjunct to the treatment of this serious, congenital 
disease. 



- 36 . 

These barely completed investigations in our own laboratories 
illustrate that the principle of application of the studies on one field 
to those of another are not isolated accidents of the past but may occur 
at any time. The astute investigator must not be restricted in his 
point of view or a valuable opportimity may go unnoticed. 

CONCLUSION 

As can be seen from the foregoing, the past year has witnessed 
important advances in almost all of the areas of responsibility of 
this Institute. Improvements are steadily being achieved in the 
treatment of specific diseases such as rheumatoid arthritis, gout and 
diabetes . In addition and even more important, there has been 
accumulated much new basic knowledge which from past experience will 
inevitably be of eventual value in some noy unpredictable area of 
categorical Interest. 



^/Y 



SUMMARY OF OPENING STATEMENT 

by 
Director, National Institute of Allergy and Infectious Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"Allergy and Infectious Disease Activities" 



Mr. Chairman and Members of the Committee: 

The budget proposal of $2^^-, 071,000 for I96O is the same as the 
1959 appropriation, but is $286,000 greater than 1959 obligation plans. 
Research by the National Institute of Allergy and Infectious Diseases 
will continue to utilize the microbiological approach fundamental to 
many of the life-saving advances of modern medicine. The year 1959 
marked an encouraging expansion of the Institute graduate training 
program, which should now help to strengthen general microbiology as 
a medical resource by providing additional trained scientists in tbis 
field, as well as in allergy- immunology and tropical medicine-parasitology, 

Among the microbial agents, viruses are the least understood. 
They are, for example, the principal agents in respiratory disease. 
For the year ending in June 1958 the National Health Survey reported 
28U million cases of disabling illness due to respiratory disease. 
The Institute continues to play a major role in research on these 
infections, which cost industry billions through absenteeism and lowered 
productivity, sharply reduce the effectiveness of our schools, and 
exact an annual tribute of $3 billion in medical bills. The hemadsorption 
viruses first isolated by the Institute, for example, were recently 



- 2 - 

sho-vm to cause widespread respiratory disease in children and adults. 
Experiments are under way on a protective vaccine. A number of other 
vaccines are being developed or improved through Institute research. 

The National Institute of Allergy and Infectious Diseases has 
increased research emphasis upon two urgent public health problems-- 
drug-resistant staphylococci epidemic today in many hospitals; and 
infections that most frequently are the cause of death in cystic 
fibrosis, a major and generally fatal disease of children. 

Highly productive research is evolving from the allergy-immunology 
program initiated 3 years ago. Blood fractions that may be involved in 
transfusion and skin grafting reactions are being characterized. 
Better methods of immunizing against ragweed pollen are being developed, 
principally through purification of allergenic extracts. 

The Middle America Research Unit (MARU) , co-sponsored by this 
Institute and the Walter Reed Army Institute of Research, is beginning 
its second year of operation in the Panama Canal Zone. This field 
laboratory recently had the opportunity to study in the Republic of 
Panama an outbreak of Eastern equine encephalitis, an insect -transmitted 
virus infection periodically epidemic in the Eastern United States. 
Army mycologists at IvIARU are studying particularly the fungus disease 
histoplasmosis, also a public health problem in the United States. 
MARU works cooperatively with the Gorgas Memorial Laboratory in Panama 
and with other health facilities in the area. 



OPENING STATEMENT 

by 

Director, National Institue of Allergy and Infectious Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 
for 
"Allergy and Infectious Diseases Activities" 



Mr. Chairman and Members of the Committee: 

The infectious disease activities at the National Institutes of 
Health evolve from the earliest Public Health Service research. 
Allergy- immunology studies were assigned in 195^ as additional program 
responsibilities ; and the Microbiological Institute became the 
National Institute of Allergy and Infectious Diseases. 

The microbiological approach underlies many of the dramatic and 
life-saving advances of modern medicine and has provided a position of 
strength from which to attack chronic disease problems. This approach 
remains fundamental to the work of the National Institute of Allergy 
and Infectious Diseases and to the progress of medicine. The I960 bud- 
get proposal for this appropriation is $2^1-^071,000 which is the same as 
1959; but $286,000 greater than the 1959 obligation plan. 

RESEiiJiCH TRAINING 

Perhaps the most encouraging development in the present year ■ 
has been the grov/th of the Institute's graduate training grants program. 
Initiated last year, the program provides grants for the support of 
special training in fields of critical scientific manpower shortage- -in 
allergy -immunology and in tropical medicine and parasitology. 



- 2 - 

The training program this year was extended to include grants in 
general microbiology^ a central discipline for the entire field of 
biology and medicine as well as for infectious and allergic diseases. 

This development brings to a close a period which has witnessed 
a gradual de-emphasis of microbiology over the last 10 to 15 years. 
As a result, the teaching of microbiology in the Nation's universities 
and in medical schools has seriously suffered and the training of 
infectious disease specialists has been largely neglected. 

What this has meant to the practice of medicine is reflected 
in the following observation made by a noted microbiologist in the 
course of a discussion on the kind of medical care now available to any- 
one who develops a serious infection. If he himself were confronted with 
this problem, the scientist said, he would be inclined to seek out a 
pediatrician or a veterinarian--the two specialists who still spend com- 
paratively large amounts of time thinking about and treating infections. 

This paucity of skills and experience needed to diagnose and treat 
human infectious diseases is illogical in view of our knowledge that most 
of man's infectious experiences are still occurring, and that what we have 
witnessed in the past decade is merely a decline in the mortality and, to 
a less extent, the morbidity of the more severe infections. Even here 
we are daily reminded of how easily such gains can be reversed. This is 
all too evident in the field of staphylococcal infections, where the 
emergence of antibiotic-resistant strains now constitute the gravest 



- 3 - 

problem confronting our hospitals. As physicians and health departments 
can testify, the same is rapidly becoming true of gonorrhea, the control 
of which is threatened by the development of penicillin-resistant strains 
of gonococcus. 

The broad significance of microbiology in the whole field of 
medicine and biology has been obscured in recent years by the emphasis 
placed on categorical disease programs. This is indicated, for example, 
in the character of medical science information which reaches the general 
public. For the most part, this is chronic disease-oriented and re- 
flects little of the excitement and challenge, the opport\uiities and 
contributions of microbiologic research. Surprisingly few clearly under- 
stand where microbiologists fit into the picture and why their skills 
are vitally needed to study infectious disease processes and to uncover 
the promising leads for the study of cancer, heart disease, neurologic 
afflictions, and other health impairments not usually associated with 
infection. 

From the time of Pasteur, microorganisms such as bacteria, yeasts, 
and molds have been recognized as agents of disease in plants and animals 
and as the catalysts of important beneficial processes in nature. The 
microbiologists, therefore, have always been interested in the life 
processes of microorganisms and their interrelations with plants and 
animals. They seek to determine how microorganisms utilize various 
nutrients for energy and for the elaboration of new cells. One branch of 



- 1^ - 

microlDiology is concerned with smaller agents of disease such as viruses: 
how they invade living cells, multiply within them, and eventually 
destroy them. 

From such studies have come important practical advances such as 
the antibiotic drugs and preventive vaccines for diseases such as 
poliomyelitis. Possibly more important from the long-range standpoint 
is the use of microorganisms as models for the study of the mechanisms 
by which all cells, including normal and malignant human cells, function. 

In view of the relative neglect of microbiology for some years, it 
is not surprising that the demand for well trained specialists in this 
field today far exceeds our meager supply. This is reflected, along with 
other teaching deficits, in the Annual Report on Medical Education in the 
United States and Canada, which includes an analysis of the budgeted, 
unfilled full-time faculty positions in the medical schools in the United 
States. 

Commenting editorially on this report, the Journal of the American 
Medical Association recently pointed out that the total number of unfilled 
full-time faculty positions in the basic and clinical sciences rose to 
619 during 1957-58^ an increase of about 90 percent over the previous 
year. This, states the Journal, "presents a problem of major concern to 
medical education. Its magnitude, unless the trend is reversed, has 
developed to the point where it may Jeopardize certain aspects of medical 
education, research, and care in the period that lies ahead. " 



- !? - 

This deficit in teaching and research training will not be 
easily overcome. But the graduate training grants program initiated 
by this Institute represents a sensible step forward. Novhere is this 
more urgently needed than in the basic sciences represented by 
microbiology. 

UPPER RESPIRATORY DISEASE 

During a one-year period ending in June 1958> the National Health 
Survey reported 2Qk million acute respiratory illnesses (such as influenza^ 
the pneumonias, and "colds") in the population of the United States. 
These conditions involved disability or medical attention. In the 
aggregate they represent a cost in billions to industry through absen- 
teeism and lowered productivity, a sharp reduction in the effectiveness 
of our schools, and a $3 billion medical bill. 

For some years this Institute has played a major role in uncovering 
viruses associated with respiratory and other illnesses, studying their 
prevalence and their characteristics, and investigating possibilities 
for immunizing against them. Research by the Institute and the military 
culminated in an adenovirus vaccine which was shown to reduce respira- 
tory disease in military recruits. During the past year, our virologists 
have applied essentially the same methods in characterizing the newly 
recognized hemadsorption viruses. They demonstrated that these agents 
are prevalent in children at certain seasons and that the virus will 
cause respiratory illness when given to adult volunteers. The laboratory 



- 6 - 
is now working on the development and trial of a hemadsorption 
virus vaccine to immunize against these prevalent respiratory 
disease agents. 

New knowledge of the microbial experiences of young children 
is unfolding in a long-term study at the Junior Village nursery of the 
District of Columbia by Institute epidemiologists and virologists. They 
are observing the exchange of infections in a study group of approx- 
imately 60 youngsters between the ages of 6 months and 3 years. As a 
result of the introduction of new disease agents by incoming children, 
and of new children to the existing agents in this group, there is much 
minor illness throughout the year. 

Data gained from this and other epidemiological studies should 
be helpful in the development of prophylactic vaccines. Whether 
immunization will prove practical depends upon factors such as (l) dis- 
covery and characterization of previously unrecognized agents, (2) deter- 
mination of which are important pathogens, and in which population 
groups, (3) development of vaccines for use against viral diseases 
important to certain groups, (h) combination of several types of important 
viruses in a single vaccine, and (5) general use of some of these 
"polyvalent" vaccines to reduce illness in the general population. 

Virologists are now able to account for about half of the formerly 
undifferentiated respiratory diseases. Still to be defined are the 
obscure causes for the remaining "common colds," bronchitis, grippe, 
atypical pneumonias and other respiratory infections. 



- 7 - 

Looking back on our experience last season with Asian influenza, 
it is worth pointing out that this was the first time that the occurrence 
of influenza epidemics had been predicted with reasonable certainty. 
This achievement was made possible by knowledge gradually assembled by 
many investigators through 25 years of research following isolation of 
the influenza virus in 1933. 

The knowledge made it possible quickly to develop and make 
commercially available Asian strain vaccine. Undoubtedly, this biologic 
greatly reduced the impact of the disease upon the people of the United 
States. 

A study undertaken by Navy scientists with our participation was 
reported recently, among a number of investigations that indicated 
considerable effectiveness of the Asian influenza vaccine in preventing 
naturally occurring influenza. The results in 3^355 Navy recruits showed 
an 83 to 90 percent reduction in febrile respiratory disease was 
associated with prior inoculation with the vaccine. 

However, millions in our general population were afflicted. 
Approximately 78,000 deaths were attributed to influenza- -many of them 
involving pregnant women or heart conditions* 

The specter of outbreaks such as the Influenza pandemic of 1918-19; 
which took an estimated 20 million lives throughout the world, continues 
to give impetus to influenza research during inter- epidemic periods. 
The Institute plans to maintain and extend research on this and other 
viral respiratory diseases during coming years. 



- 8 - 

In addition to its ovra virus studies, the Institute expects to 
spend in 1959 over $3,000,000 on virus research through grants-in-aid. 
Respiratory involvement in virus infection and basic studies of virus- 
cell interaction represent the major^ although "by no means the entire 
emphasis of this research, 

STAPHYLOCOCCAL INFECTIONS 

This Institute is deeply concerned vith the problem of 
staphylococcal disease. The causative agent is a common microbe that 
has become resistant to most of the new drugs discovered in the past 
20 years and is now the cause of serious epidemics in many hospitals. 

Although recognized principally as a problem of morbidity, a 
recent sampling indicates the death rate from this disease is appreciable, 
In a survey of one large hospital it was found that over 15 percent of 
the patients had "staph" infections, most of them acquired after 
admission, In a survey of several thousand death certificates, the 
National Office of Vital Statistics found evidence that 3 to 5 thousand 
fatalities directly or indirectly may be traced to staphylococci each 
year in the United States, 

Recognizing the need for an accelerated research effort in this 
area, the National Institute of Allergy and Infectious Diseases last 
August participated in a broad inter-study section meeting aimed at 
clearly delineating the more urgent research needs in this area. In 
September the United States Public Health Service and the National 



- 9 - 

Academy of Sciences co- sponsored a National Conference on Staphylococcal 
Disease to which the Public Health Service Communicable Disease Center 
was host. These conferences underlined the meagerness of fundamental 
information about staphylococcal disease and the great need for further 
research. Lacking better knowledge, the hospitals have had to return 
to older techniques of asepsis and more rigid controls over therapeutic 
regimen. These measures are effective in an emergency but any true 
solution will have to await extensive drug evaluations, studies of the 
basic biology of microbial resistance and host response, clarification 
of the role of the "carrier," and more adequate epidemiologic data. 

While the Institute is emphasizing its direct research effort 
in this area, it is simultaneously sponsoring an increased grants program. 
Congress last year indicated special concern over the rising incidence 
of staphylococcal illness by making available $1 million for this 
research, a five-fold increase over 1958 levels. These funds are being 
employed by university and medical center scientists in diverse studies 
of the physiological, biochemical and genetic bases of microbial resist- 
ance to drugs; on staphylococcal host-parasite relationships; on the 
nature of virulence of this organism; and on the epidemiology of hospital- 
acquired infections. 

Apparently control of drug resistance will unavoidably involve 
the most judicious use of antibiotics in hospitals. 



k 



- 10 - 
CYSTIC FIBROSIS 

Although cystic fibrosis has been recognized as a disease entity 
for just 20 years ; it has now become the second most common post-mortem 
diagnosis in children's hospitals in the United States. Nevertheless, 
the difficulties of diagnosing this disease in young infants not in 
hospitals makes current reporting and enumerating of cases unreliable. 
In view of its growing importance, the disease is receiving joint re- 
search support by the National Institute of Allergy and Infectious 
Diseases and the National Institute of Arthritis and Metabolic Diseases. 

Children with this disease have marked susceptibility to 
pulmonary infection, particularly with staphylococcal organisms. Because 
of the critical importance of infections in these patients, the major 
effort in the Institute's clinical program is directed tov/ard investi- 
gation of factors responsible for this increased susceptibility. 

Congress has appropriated additional funds for the present fiscal 
year in the grant- supported area to expand research on cystic fibrosis, 
thus enabling the grantees to attack many more of the complex problems 
associated with this disorder. Certain of these forthcoming studies 
will investigate clinical, biochemical, and genetic aspects of this 
disease. Answers in this area may provide a sound basis for eventual 
control of the disease. 



- 11 - 

To determine the actual prevalence and importance of this disease 
the Institute has requested the Children's Bureau to conduct an 
epidemiologic study on its frequency and mortality. Figures should he 
available in a subsequent report. 

A recent study by an Institute grantee estimated the average age 
at death of these patients as h years. Nevertheless, there are about 
a dozen people known to have the disease who are attending college, and 
recently a 31-yea2:-old patient was discovered. Today, with early 
diagnosis and constant care, many of these children should reach 
adolescence or beyond. 

The recent National Research Symposium on Cystic Fibrosis held 
in Washington, D. C. and co- sponsored by this Institute and the National 
Institute of Arthritis and Metabolic Diseases summarized the present 
knowledge of this disease and charted patterns for future study. This 
conference was carried out in cooperation with the National Cystic 
Fibrosis Research Foundation. 

ALLERGY- IMMUNOLOGY 

Highly productive laboratory research is evolving from the allergy- 
immunology program initiated 3 years ago. Basic studies by this 
Institute's Laboratory of Immunology are providing data fundamental to 
advances in many areas of medicine. Concomitantly, increasing numbers 
of significant findings are reported from grant- supported allergy- 
immunology research. The grants program represents a major national 



- 12 - 
effort in this long-neglected specialty. An increase of about $1 million 
brought total support to about $2 million in 1958> representing approxi- 
mately 150 grants. In 1959 grant support will approach $3 million. 

The Laboratory of Immunology has demonstrated the fallacy of 
the assumption that animals of the same species have identical and 
compatible blood serum proteins. The investigators differentiated 
between these proteins in rabbits and showed that some rabbits formed 
antibodies against sera proteins from other rabbits. Such differences 
in these minute blood components, if found in man, might help esqjlain 
immune tolerance in tissue grafting, reactions during blood transfusions, 
and possibly certain inheritance mechanisms. 

Some 5 million people with hay fever constitute a major health 
problem in the United States. Ragweed pollen is the principal allergen 
involved. The Laboratory of Immunology is fractionating this pollen by 
several methods, seeking purer extracts for deeensitization purposes. 
Research toward better diagnosis and improved prophylaxis or treatment 
of ragv;eed hay fever is also under way at 11 universities employing 
grant support totaling about $220,000. The studies are on meteorological, 
botanical, biochemical, and clinical aspects of this problem. 

MIDDLE AMERICA RESEARCH UNIT 

Established about a year ago, the Middle America Research Unit, 
staffed by scientists from this Institute and the Army, was co-authorized 
by the Department of the Army, the Panama Canal Zone Government, and the 



- 13 - 
Department of Health, Education, and Welfare. The project grev/ out of 
two practical considerations: the health care of our citizens living 
in tropical areas, and the tropical disease problems of special concern 
to the United States. It is operating under the auspices of the National 
Institutes of Health and the Walter Reed Army Institute of Research. 

The location of the laboratory in the Canal Zone is strategically 
adjacent to areas known to abound with insect-borne diseases about 
which relatively little is known or which offer particular threats to 
nonendemic countries nearby. These diseases are being studied from 
entomological, epidemiological, ecological, and virological points of 
view. Fungi prevalent in the area are also of special interest. 

The recent occurrence of an epidemic of Eastern equine 
encephalitis in the Pacora area of Panama has presented the Middle 
America Research Unit virologists with an important opportunity to 
pursue one of the major objectives of the laboratory- -an intensive study 
of the ecology of the virus to determine the vector and its reservoir. 
The periodic occurrence of Eastern equine encephalitis virus infections 
in the Middle America areas and the almost inevitable transmission to 
humans (with paralytic and perhaps fatal consequences in some cases) 
is comparable to the epidemics of this encephalitis that appear from 
time to time in the Eastern United States. 

At the request of Panama officials and in collaboration with 
Army and Gorgas Laboratory scientists, specimens have been obtained from 



- Ik - 

humans and farm animals in the area. Blood has been collected from 
domestic and wild birds. In the continuing study of various arthropods, 
some of which may transmit Eastern equine encephalitis, yellow fever 
and other viruses, more than 25,000 mosquitoes have been collected, 
including Culex, Uranotaemia, Aedes, Psorophora, Mansoni, Anopheles and 
other genera. These have been identified and frozen for subsequent 
study of arborviruses at the Institute's cooperating laboratory in 
Bethesda. 

In addition to the arborviruses, fungus diseases are a focus 
of Middle America Research Unit research. Army mycologists have 
established a project on histoplasmosis at the Canal Zone Laboratories, 
studying the serology, ecology, and epidemiology of this fungus disease. 

Histoplasmosis was first recognized and reported in Panama in 
1906 by a noted American scientist. Dr. Samuel T. Darling, The first 
concept- -that it was a rare, invariably fatal disease- -has given way 
to recognition that most cases produce no symptoms or are mild. When 
lung lesions develop they may be mistaken on X-ray for tuberculosis. 
The disease is also misdiagnosed as virus pneinnonia. It is prevalent 
in many areas of the United States, as well as in the tropics. Skin 
testing for prior exposure to Histoplasma fungi of military personnel 
arriving in the Canal Zone is one of the procedures in the 
histoplasmosis studies. 



- 15 - 

In the few months since its establishment, Middle America 
Research Unit has developed an excellent scientific staff, a 
reasonably adequate physical facility, and good working relationships 
with the numerous medical and health organizations in the Zone and the 
Republic of Panama. 

GORGAS MEMORIAL LABORATORY 

The Gorgas Memorial Laboratory was established in 1929 i^s the 
operating research facility of the Gorgas Memorial Institute of 
Tropical and Preventive Medicine, Inc. This was made possible by 
legislative action of the Congress of the United States and the 
National Assembly of the Republic of Panama. 

Staffed by medical, entomologic, virologic, and parasitologic 
scientists, the Laboratory investigates diseases of the American 
tropics. Over the years it has won a world-wide reputation for its 
contributions to new knowledge of yellow fever, malaria, and a variety 
of microbiological infestations endemic to tropical areas. 

Since the 19^8 outbreak of yellow fever in Panama, the first 
since 1905> the Gorgas Laboratory has devoted an increasing proportion 
of its time to the study of this disease, and particularly to the 
northward movement of yellow fever in monkeys and in man from Central 
into Worth America. 

In a study of the mosquito vectors of jungle yellow fever 
collected during an outbreak in Guatemala, Gorgas scientists were 



- 16 - 
able to recover yellow fever virus from three different mosquito 
species. These vere the first reported isolations from two of the 
three species. 

In addition to yellow fever, a number of other viral agents 
have been isolated from forest mosquitoes, most of which have not yet 
been classified. The study of certain of the unclassified viruses is 
being undertaken as a cooperative project between the Gorgas Laboratory 
and the newly established Middle America Research Unit. The work of 
the latter is referred to elsewhere in this report. 

The long-term study continues of the epidemiology, method of 
transmission, reservoir hosts, therapy and pathology of leishmaniasis, 
an insect-transmitted protozoan infection. Although symptoms may 
be superficial, disseminated leishmaniasis nearly always ends fatally 
if untreated. Research grants from the National Institute of 
Allergy and Infectious Diseases have further supported this work, 
and recently have been employed for field studies of the ecology 
of the sand flea Phlebotomus , a vector of leishmaniasis. In some 
areas along the Trans- Isthmian highway cases seem to be decreasing 
due to treatment of large numbers of people and to progressive 
cutting of patches of forest harboring vectors of the disease. 

Another of the important problems investigated for a number 
of years by the Gorgas Laboratory is Chagas' Disease, primarily an 
infection of forest animals transmitted by insects to man. In the 



- 17 - 
human host, the prevalence of the chronic form of this parasitic infection 
and its importance in the production of chronic heart disease have still 
to he evaluated and an effective treatment is still to he found. These 
are among the main Gorgas objectives in research on Chagas' Disease. 

The major portion of the operating funds of this Laboratory is 
supplied by United States Congressional appropriation. The amount 
requested for i960 is the same as the appropriation for 1959; $150,000^ 
the maximum allowed by an act of Congress passed in 1923 (22 U.S.C. 278). 



SIMMARY OF OPENING STATEMENT 
by 
Director, National Institute of Neurological 
Diseases and Blindness 
Public Health Service 

CCMMITTEE ON APPROPRIATIONS 
i960 ESTIMATE 
for 
"Neurology and Blindness Activities" 



Mr. ChainnEin and Members of the Committee: 

The budget proposal for i960 is the same as the 1959 appropriation, 
but $881,000 greater than the 1959 obligation plan. 

In continuing its broad attack against disorders of the brain and 
nervous system, important advances have been made this past ye3,r. The 
emphasis has been on the two extremes of age — the tragic disabilities of 
young children vho have before them a lifetime of disability, and the 
neurological disorders of advancing years which shorten productive life 
for many persons. 

Sixteen medj.cal centers across the nation are now participating 
in the Collaborative Project for Cerebral Psilsy, Mental Retardation and 
other Neurological and Sensory Disorders of Infancy and Childhood. In 
the process of studying 40,000 mothers and their babies, and assembling 
the data at the Institute, it is hoped that some of the causes of these 
disorders will be determined. This should be possible as correlations 
are made between the circumstances and events of pregnancy, labor and 
delivery and the eventual condition of the child. 



- 2 - 

Among the many iDy-products of this project has been the development 
of a neurological examination of the newborn, a psychological evaluation 
of the infant at eight months and a program for the detection of serological 
changes due to virus infection during pregnancy. 

Much progress has been made in determining the actual sensitivity 
of the nervous system to periods of asphyxia. The Institute's colony of 
monkeys in Puerto Rico has aided this project. Asphyxia, artifically 
produced in animals at birth, has made it possible to determine the extent 
and location of brain damage. 

Important advances have been made in defining with accuracy the 
area of the brain which is involved in epilepsy. It is evident that 
epileptic seizures may result from many different conditions. Some are 
caused by injury, others by interference with the normal chemical reaction 
of the brain. Several studies indicate that hormonal factors may play 
a part in influencing seizure threshold and susceptibility to convulsions. 
Other studies point to a vitamin deficiency in certain epilepsy patients 
and an interference with the proper burning of glucose in the brain tissue. 

A highly integrated and correlated Institute program is making 
progress in its investigation of disorders of muscle from the clinical, 
biochemical, and electrophysical point of view. 

Foremost among the research achievements for multiple sclerosis 
is the improved understanding of the biochemistry of the disease, its 
geographical distribution, and its possible relation to allergic 
encephalitis and viruses. 



- 3 - 

Two large cooperative projects are underway in the field of 
cerebrovascular disorders. In one, l8 Institutions are studying the 
dangerous ballooning of blood vessel walls, called aneurysms, and the 
correction of this condition by surgery before fatal hermorrhage. In 
the other project, 180O patients at seven institutions are participating 
in a study of anticoagulant drugs to prevent strokes. 

Various studies have continued at the Institute and in supported 
research centers which hold increasing hope for nerve regeneration, and 
shed new light on causes of Parkinson's disease, hearing and vision 
disorders and various other neurological disorders. 

Because of the serious shortage of scientists in neurology and 
related disciplines, the progress of the Institute's training program 
has had vital significance to the entire area of neurology. Eighty to 
ninety persons now are being trained as specialists in clinical neurology. 
Training grants in ophthalmology, otolaryngology, and neurological sciences 
have increased and approximately 125 special trainees (MD's and PhD's) 
supported at 50 institutions. 

The Institute's international programs have included a study in 
New Guinea of "kuru, " a fatal neurological disease; epidemiological studies 
of multiple sclerosis in Japan and encephalitis in Guam; and the 
Institute's active participation in the World Federation of Neurology 
with representatives from neurological societies in more than 30 countries 
around the world. 



OPENING STATEMENT 
oj 
Director^ National Institute of Neurological Diseases and Blindness 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"National Institute of Neurological Diseases and Blindness" 



Mr. Chairman and Members of the Committee: 

This statement will review for the Committee the progress which 
the National Institute of Neurological Diseases and Blindness has made 
in research and training during the past year. The I96O budget pro- 
posal for this appropriation is $29,^03,000 which is the same as 1959; 
but $881,000 greater than the 1959 obligation plan. 

Neurology is a relatively new branch of medicine -- barely a 
century old. It is bristling with unsolved problems of which doctors 
and related scientists are painfully aware. The problems faced are not 
new but they are an increasing threat to the Nation because of their 
magnitude . 

Medical developments of the last twenty years, particularly 
antibiotics and immunological techniques, have brought an almost 
incredible reduction in infant mortality from acute infectious diseases. 
Epidemics have been brought under control and many who formerly would 
have died from pneumonia in middle age are now living long past sixty- 
five. The control of chronic diseases, of which diseases of the brain 
and nervous system are a large proportion, however, has not kept pace. 



- 2 - 

At both ends of the scale, the number of children and of persons past 
sixty-five with neurological disorders has increased. In 1910^ for 
example, four times as many children died from summer diarrhea as from 
congenital malformation. In 19^6, the ratio was almost reversed. 

The impact of neurological disorders, a large percentage of 
which are chronic illnesses, is felt by the entire family and often the 
community. Because of the excessive burden of such diseases, many 
families become impoverished and are forced into dependency. The 
social impact of these chronic Illnesses is thus felt as a blow to our 
whole economy. 

Among the many neurological and sensory disorders are those of 
infancy and childhood such as cerebral palsy, mental retardation, con- 
genital malformations, muscular dystrophy, and epilepsy; the diseases of 
middle age such as multiple sclerosis and other demyelinating diseases; 
and the diseases of later life such as Parkinson's disease and cerebro- 
vascular diseases. The disorders of sight, speech, and hearing are 
particularly pronounced both in childhood and old age. 

Research at the present time appears to offer an outstanding 
challenge at the extremes in the life cycle — those disorders par- 
ticularly affecting infancy and old age -- cerebral palsy and mental 
retardation, brain strokes and sensory disorders. 

Some of the Institute's accomplishments in these and other 
major areas follow. 



- 3 - 

CEREBRAL PALSY 

Cerebral palsy is not a siugle disease but represents symptoms 
resulting from many causes. In order to determine and prevent these 
causes, it is essential that a classification of the various forms of 
cerebral palsy be established, and the ability to differentiate among 
the varieties be developed. 

The Institute has recognized the importance of such differ- 
entiation and during the past three years has established a number of 
programs to aid in this differentiation. This program will depend, to 
a large extent, upon the careful examination after death of the damaged 
brains of cerebral palsied individuals. Such neuropathological exami- 
nations are presently being conducted in five different centers 
throughout the United States and the results are beginning to provide 
valuable information. 

Progress also is being made in the clinical differentiation of 
cerebral palsy. Institute grantees have reported recently on the differ- 
entiation of two large groups of cerebral palsied children. Those 
with symmetrical involvement of the lower extremities without other 
evidences of localized injury of the brain were especially separated from 
the group. It was found that a large percentage of these children had 
been premature at the time of birth. This has suggested some specific 
mechanism through which prematurity leads to this rather characteristic 
type of symmetrical paralysis and has opened an important avenue for 
further research. 



. k - 

The second major concern in determining the causes of cerebral 
palsy is the establishment of correlations between the circumstances 
and events of pregnancy^ labor, and delivery, and the eventual condition 
of the child. Previous efforts to establish a reliable cause-and-effect 
relationship have failed. This has been due largely to the time lapse 
between the occurrence of fetal injury and the recognition of the in- 
jury. The recognition is often not possible until several years after 
birth. 

The collaborative project for the study of perinatal morbidity 
has been developed in an attempt to solve this difficult problem, 
vrithin this study, which now involves the collaborative efforts of l6 
different institutions, over 40,000 women will have detailed obser- 
vations throughout pregnancy, and their children will be observed long 
enough to determine whether, in fact, there has been an injury occuring 
during pregnancy. This project, which is of fundamental importance in 
relation to cerebral palsy, is equally significant in relation to 
mental retardation and the congenital forms of blindness and hearing 
loss. 

Important by-products already are stemming from this program. A 
series of examinations has now been developed in order to conduct the 
study with precision and reliability. These examinations must be relied 
upon to detect and define the factors during pregnancy causing abnor- 
malities of the offspring. They include such items as methods for 



- 5 - 

obtaining accurate and detailed knowledge of the family history; an 
evaluation of the emotional stability of the pregnant woman and her 
general health, social, and economic status; the detection and evalu- 
ation of specific diseases and complications of pregnancy; observation 
and detailed recording of the events of labor and pregnancy; a neuro- 
logical examination for the newborn; a psychological evaluation of the 
infant at eight months; and a program for the detection of serological 
changes due to virus infection during pregnancy. Many of these methods 
have been subjected to careful pretest during the last year, and early 
in 1959 the collection of data in accordance with this protocol will be 
underway . 

Meanwhile, a more detailed exploration of factors already known 
to be capable of producing injury of the baby are in progress. An 
important cause of neurological damage in the past has been jaundice of 
the newborn infant. The gradual conquest of this crippling condition 
represents a thrilling story. The first important step toward its 
conquest was the discovery of the importance of Eh incompatibility. 
This was followed promptly by a recognition that it was possible, by 
exchange transfusion, to wash out of the baby's body the harmful anti- 
bodies received from the mother, to replace the destroyed red blood cells 
with new ones, and to give the infant a fresh start through the pre- 
carious first days of life. 



- 6 - 

Unfortunately, cases of jaundice are still occurring and exchange 
transfusion is not without its hazards. The present attack is directed 
to determining the mechanism through which the "bile pigments circulating 
in the blood stream are able to injure or destroy the brain. Why, for 
example, do some infants with a relatively small amount of bile in their 
bloodstream suffer severe brain injury, while others with a higher 
bilirubin level go unscathed? 

An important clue regarding this question has been developed by 
a grantee in the course of studies on the effectiveness of certain anti- 
biotic agents in the treatment of infections of premature infants. He 
discovered that children treated with sulfonamides were likely to 
develop kernicterus even though the level of bile in the blood was not 
significantly increased by this treatment. Apparently, the sulfonamides 
made it more likely for the brain to be injured by this toxic product. 

During the past year, the mechanism through which this compound 
is able to increase the likelihood of brain damage in the jaundiced 
infant has been further elucidated. It has been found that a large 
amount of the bilirubin normally remains combined with certain proteins 
in the bloodstream, and is not able to permeate the capillaries into 
the brain tissues to produce damage. If the blood proteins, however, 
are low, or if the sulfonamides displace the bile pigments from the 
protein, a large amoun-fc of free toxin is available, leaks through the 



; •' 



capillary walls, and damages the braia. The level of serum protein, 
therefore, is an important factor in determining whether or not the 
brain of the jaundiced infant will be injured. 

In other approaches to this same problem, investigators are 
studying the method by which the bile pigments are detoxified and 
excreted as well as the actual chemical reactions which take place 
between the toxic bile pigment and the brain tissue. 

As a result of this series of investigations, the frequency with 
which the newborn infants are damaged by jaundice in the newborn period 
(an important cause of cerebral palsy) has been reduced well below two 
thirds. The additional discoveries which will stem from the more recent 
knowledge can be expected to reduce this still further in the near 
future . 

A significant program contributing toward the elucidation of 
the mechanism of brain injury is the Institute's perinatal project in 
Puerto Rico. Here a monkey colony has been established with over 70 
breeding females in whom the course of pregnancy can be studied and 
experimentation performed. The actual sensitivity of the nervous system 
to periods of asphyxia, artificially produced in these animals at the 
time of birth, has been subject to investigation, and the extent and 
location of the brain damage which results is now clearly delineated. 
The importance of nutritional, toxic, and endocrine factors during 
pregnancy is the next subject for investigation in this colony. Investi- 
gators from many research centers are cooperating with this project. 



- 8 - 

This year^ a special project has been developed to determine 
whether Asian influenza infection during pregnancy may lead to fetal 
injury. Preliminary reports from approximately 8000 women have not 
indicated fetal injury. It is still to early, however , to know whether 
an increase in congenital defects, such as occ\irs following maternal 
infection with German measles, occurs also with the Asian influenza 
virus . 

Underlying the problem of cerebral palsy is the whole question 
of factors which interfere with the normal development of the unborn 
child. The Institute is supporting a broad program in human embryology 
in which the mechanism of normal development is under investigation. 
Using X-ray or toxins, it has been demonstrated that the human embryo 
undergoes certain phases during which it is extremely sensitive to 
injury. In the human, the first two months of pregnancy appear to 
be a particularly critical time. An interesting method for determining 
the time at which injury has occurred to the unborn child has been 
found to be an examination of dental enamel. Grantees have discovered 
that by examining the teeth of cerebral palsied and mentally defective 
children, one can observe ridges corresponding with the stage of 
development at which injury occurred, and accurate timing of the date 
of this injury during pregnancy may thus be achieved. 

MENTAL RETARDATION 

From a position of public neglect and scientific hopelessness, 
thu attack on mental retardation has forged forward to a dynamic status 



- 9 - 
in the past few years. Many programd ai-'e now underway to aid in the 
prevention and treatment of mental retardation. One of these is the 
Institute's broadscale collaborative study relating to both cerebral 
palsy and mental retardation described above. 

In laboratory research, the biochemistry of the body comprises 
one of the most hopeful fields of study. Several such studies are 
supported by the Institute. In one, the blood ammonia levels have been 
investigated. In others, investigations are under way concerning heme 
and bile pigment metabolism in infants; nitrogen metabolism of nervous 
tissues; and a chemical study of congenital mental defects. 

Accounts of newly discovered defects in inborn body chemistry are 
bringing with them methods of treatment by diet which promise prevention 
of some types of mental retardation. While only a small percentage of 
all mental retardation has so far been shown to arise from such causes, 
-i need for continued research in the biochemistry of the brain is 
evident o-nd the actual extent of this problem is unkno^ra. 

The known biochemical types of mental retardation may be related 
to disturbances in the chemical characteristics of body protein, 
carbohydrate, fat or of hormones. Three distinct forms of mental 
retardation are linked with inherited disorders of protein metabolism. 
They include phenylketonuria for which study is active on a special 
preventive diet known as the "low- phenylalanine diet;" "H" disease; and 
hepatolenticular degeneration (Wilson's disease). 



- 10 - 

Loag-knovm is the mental retardation of the cretin, involved with 
lack of iodine and thyriod hormone. Now cretinism is recognized as a 
group of hormone-defect ailments. The effect of thyroid hormone for 
prevention of associated mental retardation is still controversial, "but 
its use for patients is worth evaluation, and research may provide more 
specific answers . 

The recognition of previously unknown abnormalities of body 
chemistry among the retarded is thus a major problem. This year the 
Institute has launched a new program in this area utilizing the sensi- 
tivity of certain bacteria to the presence of complicated compounds 
whose excretion in small amounts may be overlooked by the usual chemical 
techniques. 

In the realm of treatment, the use of glutamic acid as a possible 
treatment to raise the IQ of the mentally retarded remains debatable 
after more than 10 years of study. Further research will seek conclusive 
mswers . 

Also in the treatment phase, the Institute has made successful 
efforts to promote studies in speech disorders as related to mental 
retardation and other neurological problems. Eight such projects were 
started in 1958. 

EPILEPSY 

Research directed toward the surgical and medical control of 
epileptic seizures is continuing. Important advances have been made in 



- 11 - 

defining with accuracy the area of the brain which is involved. This 
is essential in removing the epileptic foci from which siezures may- 
originate . 

A recent monograph on seizure patterns shows that artificially 
induced seizures in patients suffering from epilepsy have made it 
possible to describe with accuracy the seizure pattern, and to correlj-te 
the observed movements with the abnormal area of brain activity. Also 
this type of investigation has extended further through the use of 
depth recording techniques. New instruments make it possible for an 
extremely fine wire to be inserted into the substance of the brain and 
through this wire to record the minute electrical discharges which appear 
to be associated with the currents of the seizure. Using this tech- 
nique, it was found that certain seizures which were attributed to the 
temporal lobe actually originate from the inner surface of the frontal 
lobe. The extension of these methods may improve the accuracy of surgi- 
cal removal which is already proving effective in certain clearly 
defined seizure types. 

These studies also are making possible a much more accurate 
description of the disturbances of intellectual functions which are 
occasioned by the presence of irritated or destructive lesions in the 
brain. The artificial production of similar areas of destruction in 
the brains of monkeys is a useful addition, giving parallel informatioa 
regarding the types of disturbances of behavior which are to be 
anticipated. 



- 12 - 

An excellent compilation of the various aspects of temporal lobe 
epilepsy is now available in a book containing the proceedings of the 
Second Colloquium sponsored by the Institute in 1957* 

Several approaches to the problem of the chemical control of 
seizures are being undertaken. In a series of patients treated with 
cortico-ateroid hormones for unrelated diseases, it was noted that 
changes in the electroencephalogram (pattern of brain electrical 
activity) were present. Specifically, these patients showed a heightened 
response to certain forms of stimulation, indicating increased irrita- 
bility of the brain. It is evident that hormonal factors may play a 
part in influencing seizure threshold and susceptibility to convulsions. 
Further investigations are needed to determine the extent to which these 
influence the occurrence of seizures in epileptic patients. 

In the search for new drugs capable of controlling seizures, 
increasing attention is being directed toward those agents and enzymes 
capable of influencing the normal metabolic and chemical processes within 
the brain. It has recently been discovered, for example, that an in- 
hibitor of monamine oxidase is capable of influencing seizure threshold. 
A carefully controlled study is now underway and will continue for tht 
next six months. At the end of that time it should be possible to 
determine whether this agent actually will influence seizure patterns . 

A further study of metabolic reactions in epileptic patients 
centers around the known occurrence of eiezures in individuals who are 



- 13 - 
lacking in the vitamin, "pyridoxine. " This seizure state is related by 
interference with the proper burning of glucose in the brain tissue. By 
the use of radioactive tracer techniques, it is becoming possible to 
determine the exact nature of the blocked chemical reactions, and efforts 
are now in progress to determine what agents or chemicals might be admin- 
istered to such patients to overcome the blocks. 

It is evident that epileptic seizures may result from many differ- 
ent conditions -- some associated with actual brain injury, others with 
interference with the normal chemical reactions of the brain. The 
eventual solution of this complex problem will depend upon the ability to 
recognize and define in each individual patient the nature of the de- 
fective reaction, and to correct it with the drug or agent which is 
most capable of restoring a normal situation. Prompt testing of newly 
developed agents is also essential. 

DISEASES OF MUSCLE 

Disorders of muscle fall within three general categories: 
diseases of the muscle itself, or muscular dystrophies, in which the 
muscle tissue seems to be diseased or destroyed; disorders affecting 
the muscle exciting system and the initiation of muscle contraction - 
myasthenia gravis and certain familial periodic paralysis disorders; and 
inflammation of the muscle knovra as myositis. 

In the past it has been extremely difficult to differentiate 
among these major categories, and even more complex to attempt to 



differentiate various entities within the categories. The study of 
these diseases has, therefore, required a highly correlated and inte- 
grated program in which patients with muscle diseases are studied from. 
the clinical, biochemical, and electrophysical point of view. The 
development of such a multidiscipllnary approach has been a unique 
opportunity of the intramural program of the National Institute of 
Neurological Diseases and Blindness and it has been one of the out- 
standing parts of the intramural program. 

The first approach has been a neuropathological one — the 
anatomical study of muscle tissue in normal and diseased states. The 
Atlas of Muscle Pathology published last year has been an outcome of 
this approach. This year a special study was made of 23 infants 
suffering from muscle weakness in the early months of life. The careful 
clinical and pathological examinations of these children have indicated 
that they comprise in fact five different diseases which until now have 
been confused as a single entity. 

The ability to differentiate fundamental abnormalities is being 
increased through the utilization of the electron microscope. Capable 
of detecting minor structural changes, it has already demonstrated that 
in the myotonic form of dystrophy there is an unusual increase in the 
RNA elements — an important compound of all living cells. 

Closely correlated with these studies of structure of muscle are 
special investigations concerning the motor and sensory nerves which 



- 15 - 
play an important role in muscle activity. New stains have been 
developed through which the fine nerve terminations can be seen. In 
muscle paralysis stemming from injury of the nerve, it has been demon- 
strated that regeneration of these fine nerve endings can take place in 
association with the healing process. It has not yet been determined to 
what extent nerve and muscle can regenerate in the case of primary 
diseases of muscle. 

Important chemical studies are underway regarding the nature of 
the protein compounds of the muscle in health and disease. It is the 
compounds "actin" and "tropomyosin" which play an important part in the 
muscle contractile process, and which are presumed to be abnormal in 
the case of the muscular dystrophies. It is now clearly evident that 
there is an abnormal protein content in dystrophic muscle. The actual 
distribution of this protein is being studied by the use of fluorescent- 
labelled elements, through radioactive tracers, and through the develop- 
ment of specific antibodies which carry a dye directly to the specific 
protein molecules under investigation. Through such studies it will be 
possible to determine with accuracy the actual abnormal molecules in the 
diseased muscle, and hopefully to determine ways in which these elements 
can be modified. 

A special investigation this year has centered around the defects 
of muscle excitation which occur periodically in "familial periodic 
paralysis." This has included a simultaneous study of the clinical 
progress of the disease; the level of certain important hormones such as 
gonadotropic, corticoids and ketosteroids; alteration in the ionic 



- 16 - 

balance of sodium and potassium in the muscle fiber and the surrounding 
fluids; the microscopic appearance of the muscle during periods of 
paralysis as compared with appearance during periods of normal activity; 
and the electrical activity of the muscle as demonstrated by the use of 
fine intracellular needle electrodes. The outstanding development in 
association with these studies has been the demonstration that during the 
period of paralysis there is a large accumulation of intracellular fluid 
without a significant change in the ionic balance. Also, during this 
period, the muscle becomes electrically unexcitable. More information 
regarding these changes in ionic balance is essential. It is known that 
there is decreased potassium excretion in the urine preceding an attack, 
and that in many cases an administration of potass ii«n has a very 
beneficial clinical effect. 

In myasthenia gravis, the major concern still relates to the 
mechanism by which the nerve impulse fails to reach the muscle fiber in 
order to initiate a voluntary contraction. The demonstration a number of 
years ago that the picture of myasthenia gravis can be reproduced by the 
administration of curare (Indian arrow poison), and that striking 
amelioration both of curare poisoning and myasthenia gravis by certain 
antagonistic (anticholinesterase) drugs has provided a basis for investi- 
gating the nature of the defect. 

This Institute is conducting an active program of testing of a 
number of anticholinesterase drugs, including "galanthamine, " which 



- 17 - 
has been isolated from an alkaloid in the U.S.S.R. and utilized in the 
treatment of myasthenia gravis. Through comparison of the action of 
various such compounds with the abnormalities observed in myasthenia 
gravis^ an effort is being made to determine which of these drugs may 
be the most effective in treatment of this disorder^ and to search for 
the abnormal chemical whose presence in cases of myasthenia gravis has 
long been suspected. It is still not certain whether the block results 
from the existence of some "toxic" agent such as curare, or whether it 
represents an inadequacy of liberation of a transmitter substance, its 
rapid destruction, or some failure of the excitable muscle fiber to 
react normally to this substance. The elucidation of this problem will 
require a continuing program of search for new compounds, and of critical 
analysis of the content, location and nature of the several compounds in 
the human body which relate to the transmitting process. 

MULTIPLE SCLEROSIS 

Foremost among the research achievements for multiple sclerosis 
is the improved understanding of the biochemistry of the disease, its 
geographical distribution, and its possible relation to allergic enceph- 
alitis and viruses. 

Earlier reports to Congress revealed discoveries relating to 
myelin which normally insulates the nerves but disappears in scattered 
patches in multiple sclerosis. This research included information 
concerning the synthesis of sphingosine, an essential compound in the 



- 18 - 
fat of the myelin sheath around nerves. This year, a new mechanism was 
discovered for the lengthening of carbon chains leading to a product 
which subsequently is oxidized to sphingosine. 

In a new project, serum from patients with multiple sclerosis will 
be examined for the presence of specific antibodies against certain com- 
pounds (antigens) which are hostile to tissue fats. 

New information has been found concerning an enzyme related to 
deymelinization. The long name for this enzyme is Butylchoninesterase. 
The investigators studied its distribution in the central nervous system 
of several common animals. In several animals, this enzyme occurs in the 
lining cells (endothelium) of internal organs. But in the cat and fowl, 
investigators discovered it in those important satellite cells which 
originate myelin. 

The opponents or inhibitors of this enzyme have been reported to 
cause the loss of myelin in fowl, Hence, here is a hopeful suggestion of 
relationship between this enzyme and the formation of myelin. If 
scientists can learn why myelin disappears in muJ.tiple sclerosis, they 
may eventually learn how to prevent its disappearance. This would be a 
major step in solving the problem of multiple sclerosis. 

The neuroglia or so-called glue cells have long been known for 
their support of brain structure. But recent studies of neuroglia in 
tissue culture and under the electron microscope now reveal that they 
play more than a supporting role. In fact, research indicated that they 



- 19 - 
fill an important role in the formation and maintenance of myelin. 
Reports this year include descriptions of exciting new techniques of 
electron microscopy, improved silver staining of nerve fibers, and 
growth of nerve cells in tissue cultures in test tubes providing new 
foundations for research on the brain and nervous tissue. 

The geographical distribution of multiple sclerosis, as reported 
last year, reveals that multiple sclerosis is far more common in 
northern United States than in the southern part of the country, The 
prevalence of multiple sclerosis in Japan has now been investigated, as 
well as incidence in various city and rural areas . 

The long-term project on the effect of climate after multiple 
sclerosis has occurred probably will be reported by the end of 1959' 
The three agencies cooperating in this research are the National 
Institute of Neurological Diseases and Blindness, the National Research 
Council Follov;-up Agency, and the Veterans Administration. 

As reported earlier to Congress, animals may be given an ailment 
with symptoms like those of multiple sclerosis. This is an "experimental 
allergic encephalomyelitis." 

No Institute studies seeking a possible germ cause for multiple 
sclerosis show any indication of a spirochete as a cause. However, the 
similarity of experimental encephalitis in aminals stimulates the search 
for a possible virus as a cause. 



- 20 - 
CEREBROVASCULAR DISEASES 

Progress was made this year against the third- ranking killer and 
foremost adult crippler, "cerebrovascular diseases." "Stroke" is the 
popular name for the largest of this group of ailments. 

The term, "cerebrovascular diseases/' was agreed upon by a 
committee of experts appointed by the National Institute of Neurological 
Diseases and Blindness in 1955 to expedite progress in research on the 
"stroke" problem. This group decided a primary need was a common 
language in order for investigators and physicians to be able to pool 
their data for research. Their 3^ page study provides the first 
classification and definition in one source of all known types of 
cerebrovascular diseases^ and reprints are available from the Institute- 
to medical men and scientists. 

Meanwhile, the two large cooperative projects continue. In one of 
these, l8 institutions are studying the dangerous ballooning of blood 
vessel walls called aneurysms and the correction of this condition by 
surgery before fatal hemorrhage. First reports are anticipated toward 
the end of 1959. 

The second large project in the brain stroke field is the study 
of anticoagulant drugs to prevent strokes, or avoid other strokes after 
one has occurred. The largeness of the study, which is following about 
l800 patients at 7 institutions, is expected to provide much more rapid 
judgment than would be possible at any one hospital center. 



- 21 - 

In addition to this direct work with patients, laboratory research 
is making progress . The challenging field of fluid movement between 
blood vessels and brain is being clarified by modern techniques using 
harmless radioactive tracers; and the narrowing of brain arteries is 
being studied. Scientists have begun a systematic study of a large 
series of subjects. Investigators carefully evaluate the location and 
the degree of narrowing of the brain arteries of all sizes. A study 
of the different-sized blood vessels of the brain of patients in this 
country has now been completed, and provides a baseline for comparison 
on which to expand this study to an international scope. 

PARKINSON'S DISEASE 

Research supported by the Institute at various institutions shows 
a well-diversified attack on Parkinson problems, and related types of 
involuntary movements. These include studies on the structure of nerve 
connections in the area affected in Parkinson's; on the functioning of 
that area; and on tremor which is a major disability in Parkinson's. 
All research on aging in the human nervous system may prove helpful in 
this ailment as its symptoms are associated with aging. 

Parkinsonism is a symptom which may actually be associated with 
several different disease conditions. For example, many cases were 
clearly a delayed aftereffect of the 1918 influenza epidemic. In other 
institutions, a familial pattern has been observed. This year, the 



- 22 - 
Institute has launched an epidemiological program to study these factors. 
Preliminary reports indicate that there are over 300^000 patients with 
Parkinsonism in the United States. 

Positive progress in surgery for Parkinsonism, the National 
Institute of Neurological Diseases and Blindness supported, appears as 
continual surgical variations and refinements are found to be involved 
with shaking and rigidness. At present, successful surgery requires 
careful selection of patients, with the younger and stronger ones most 
likely to be benefitted. Urgently needed is effective surgery for the 
elderly or severely afflicted Parkinson patient. Surgery of the type 
used for Parkinson tremor and rigidity also helps some types of cerebral 
palsy patients. 

Medical research continues for the best combination of drugs to 
control Parkinson symptoms. Both medical and surgical research adding 
to the general knowledge of the brain and how it functions is providing 
helpful information relative to Parkinson's disease. 

REGENmATION IN THE NERVOUS SYSTEM 

The important studies in regeneration of the spinal cord outlined 
last year are being carried forward in several laboratories. It is too 
early, however, to evaluate the results since regeneration takes many 
months to occur. An interesting related development is the discovery 
that in lower animals in which the diaphragm has been paralyzed by 
nerve injury, restoration of function can be accomplished by substitution 



- 23 - 
of another uninjured nerve. Experiments have been initiated to determine 
whether this can also be accomplished in humans with respiratory 
paralysis after poliomyelitis or related disorders. 

ENCEPHALITIS 

Many conditions may cause encephalitis or brain fever. In fact^ 
by definition any inflammation of the brain falls within this category. 
Because the clinical symptoms and course of many different conditions 
causing inflammatory reactions on the brain may be similar, it is often 
difficult to determine whether the causes are virus infections, allergic 
reactions, or toxic and deficiency states. 

At a symposium on "Sequelae of the Arthropod-Borne Encephalitides, " 
sponsored by the Institute, investigators assessed what is known about 
the aftereffects of brain inflammations caused by mosquitoes and other 
insect-borne viruses. It is evident that it is necessary to have a more 
accurate determination of specific responsible viruses, a clearer 
definition of the nature of the brain inflammation, and some precise 
methods for assessing the subsequent brain damage. 

The 1918 influenza epidemic, as mentioned above, was followed by 
severe long-lasting neurologic residuals. However, the specific virus 
which was responsible for this disease has never been isolated. The full 
evaluation of the long-lasting aftermaths of the disease has not yet 
been achieved. This was especially true since many individuals afflicted 
by this disease developed, as a sequelae, severe and serious changes in 
behavior without any clear-cut intellectual or physical impairment. 



- 2h - 

A recent study by Institute investigators of the aftereffects of 
a severe epidemic of mosquitoe-borne encephalitis in Guam shows a 
relatively high occurrence of subsequent intellectual impairment, 
physical disability, and epilepsy. There is considerable evidence today 
that some ot the minor virus diseases of infancy such as measles and 
mumps, vhich are not infrequently associated with encephalitis, have 
more serious sequelae than was previously recognized. Brain wave studies 
suggest that minor brain damage accompanies these illnesses. 

New methods of virus culture are improving our ability to 
isolate and classify the viruses responsible for these diseases. To be 
effective, however, such studies must be carried out on a worldwide 
scale since the distribution of viruses varies from country to country 
with epidemics spreading as the virus is carried abroad. For comparable 
studies to be carried out in different countries, a common terminology 
and classification of the disease processes themselves is needed. To 
this end, a grant has been made to the World Federation of Neurology for 
the conduct of a conference concerning the brain tissue of individuals 
dying with various types of encephalitis in order to classify the various 
disease patterns. 

In some forms of encephalitis many hundreds of individuals may 
be sick for each patient who actually develops brain disease. Why this 
is so is not known. Studies of the blood-brain barrier--the protective 
membrane which prevents the transfer of some infectious agents from the 



- 25 - 
bloodstream into the brain — are providing more information as to hov the 
brain is changed by infections and toxins. Equally important is the 
study of the sensitivity and inflammatory reactions which the brain ex- 
hibits when exposed to infection. The nature of the inflammatory 
reaction in acute encephalitis is important since in many cases it 
appears that the inflammatory reaction actually produces more brain 
damage than does the infectious agent itself. Efforts to modify this 
inflammation in certain bacterial infections such as tuberculosis are 
very encouraging. 

DISORDERS OF HEARING 
Over the past ten years, major advances in our knowledge of the 
basic structure of the ear and of the pathways over which sound is con- 
ducted to the central nervous system have gradually developed. Through 
electrophysiological techniques, it is possible to trace the passage of 
a sound impulse from the eardrum to the nerve receptor organs in the in- 
ternal ear, and then to the area of the brain where the sound is received 
and interpreted. We reported last year on the discovery of an important 
new pathway- -through which the brain itself is able to control the 
sensitivity of the ear and modify its perceptive acuity. Important new 
studies are using highly trained animals "conditioned" to respond to a 
sound with a highly organized pattern, a pattern depending upon the 
animal's ability to recognize pitch, loudness, quality or location of 
sound. In these animals, one can determine the dificit which results 



- 26 - 

when specific brain areas are s\;irgically removed. Such procedures are 
demonstrating the areas of the brain which are concerned with the 
interpretation of sounds, as well as the quality of behavior disturbances 
and the responses which result when these areas are injured. More infor- 
mation of this sort is needed if we are to understand the varied and 
complex patterns of deafness. 

Investigations are in progress to determine how hearing mechanisms 
are damaged. The first of these studies has to do with prenatal hearing 
loss. The collaborative project on perinatal morbidity studies the pre-- 
natal factors and the conditions which may cause impaired hearing. Each 
child born during this study will be given careful otological exami- 
nations; and the presence of any abnormality will be correlated with 
factors in the history of the pregnancy and delivery which might be 
responsible. 

Careful anatomical examinations of children dying at birth or in 
early infancy in whom hearing loss is suspected contribute to our 
knowledge of the mechanisms causing the damage. It is known, for example, 
that jaundice of the newborn infant, German measles during pregnancy, 
and maternal diabetes are frequently associated with deafness. 

Certain forms of deafness are hereditary. Careful studies of the 
family tree of these hereditary forms of deafness are helping to elucidate 
the mechanisms of their action. Several strains of mice which have 
genetic hearing abnormalities are furnishing valuable clues to the 
mechanism of genetic deafness. 



- 27 - 

Several postnatal causes of deafness are knovn; streptomycin and 
quinine are drugs known to produce hearing loss. The affects of adminis- 
tration of large doses of these drugs are now being determined; and the 
actual structural damage which they produce is being demonstrated in the 
ear by careful microscopic techniques, including the electron microscope. 

Changes in fluid balance in the ear and the development of 
swelling around this sensitive organ are also known to cause deafness. 
These mechanisms are being studied again in animals, by artificial 
hydration experiments. Meanwhile changes in circulation patterns which 
may also relate to this abnormal fluid collection are under investi- 
gation. 

Our future understanding of deafness and the development of proper 
training techniques, depends upon the recognition of the specific form 
of deafness present in any given individual- -that is whether such deaf- 
ness is due to damage to the ear, the nerve, the brain stem, or to the 
higher brain centers. At present, it is difficult to be certain whether 
an individual is or is not deaf, especially in early infancy. The 
American Academy of Ophtahlmology and Otolaryngology has initiated a 
national program aimed at developing methods for early identification of 
deafness and of the diseases causing ear damage. 

There are now being supported several programs evaluating specific 
hearing tests, including the galvanic skin response, and the electro- 
encephalographic response to an auditory stimulus. Finer judgments of 



- 28 - 
the quality of sound, such as pitch, rhythm, and localization in space 
are also being evaluated in individuals shoving evidences of hearing 
impairment or speech defect. The Institute also has two field investi- 
gations of training methods for the deaf. 

Two other significant field investigations are concerned with 
demonstrating changes in hearing as they progress with old age. A 
common cause of loss of hearing in the older age groups is "otosclerosis," 
a condition in which the bones become stiffened and no longer are 
capable of vibrating in the ear. Surgical relief offers hope that these 
stiffened bones may once again be made to vibrate. These techniques 
are being evaluated in man and animals by meticulous examination of 
bones removed at operation, and by the study in animals of the healing 
process which takes place following operative procedures. 

The whole field of hearing research is ready for rapid development 
but the training of more skilled investigators will be required if the 
new highly specialized instruments and techniques are to be accurately 
exploited. 

VISUAL DISORDERS 

The research program of the Institute relative to visual dis- 
orders includes research relating to: cataracts, glaucoma, retinopathy, 
keratitis, uveitis and other inflammatory and parasitic diseases of the 
eye; metabolic and degenerative disorders of the eye; strabismus and 
neuromuscular disorders and other ophthalmologic disorders including 
injuries. 



- 29 - 

A considerable amount of basic research is aimed at understanding 
the mechanism of vision, transmission of visual impulses and cerebral 
appreciation of visual stimuli. 

Research relating to cornea transplants indicates that, if 
properly preserved, corneas can be used even after two years of storage. 
Use in over 50 patients shows that the preserved corneas are as good as 
fresh corneas for similar transplantation. The best means of preser- 
vation was found to be by dehydrating them with pure glycerine, sealing, 
and storing in vacuo at room temperature. Methods have also been 
developed for preserving vitreous humor for use in specialized problems 
of retinal detachments. 

Various studies of the lens tissue of the eye have shed light on 
the problems of cataracts. A comparative age study, using rabbit lenses, 
supports the general theory that metabolic activity of the lens decreases 
with advancing age. Also, medium doses of irradiation have usually led 
to cataract formation. 

A collaborative project, in which the Institute acts as coordi- 
nating agency for a number of nonfederal research facilities, is now 
underway to investigate the incidence, causes, and treatment of uveitis. 
This project is being supported to the extent of $U3,000. 

Plans for a collaborative study of glaucoma are being developed 
by the Institute in conjunction with the Division of Special Health 
Services, Chronic Disease Program of the Bureau of State Services, 



- 30 - 
Public Health Service, and four research institutions interested in 
this subject. The study will evaluate glaucoma detection and diagnostic 
procedures . 

Aside from these specific visual research activities, a large 
number of projects in which serious visual disturbances may be inci- 
dental to neurological disease are being supported. These include the 
extensive collaborative study in cerebral palsy and other neurological 
defects of infancy, studies of aneurysms and subarachnoid hemorrhage and 
studies of the incidence, diagnosis, and causative factors of brain 
tumors , 

KURU 

Since 1956 the Institute has been supporting an extensive field 
study of the problem of kuru. This rapidly fatal disease of the nervous 
system has been discovered in an isolated population living in the 
inland plateaus of New Guinea. It bears many resemblances to certain 
disorders of the nervous system known in the civilized world, but has 
certain distinctive features. 

Within the Isolated valley where this disorder exists, the study 
has ferreted out approximately 98 percent of the existing cases, and has 
records of most instances which have occurred within this generation. 
The disorder has an extremely high incidence, affecting approximately 
2 percent of the population each year, and probably accounted for over 50 
percent of the deaths. For each examined case, detailed history has been 
recorded. 



- 31 - 

The successful acceptance of the research team among this 
primitive tribe has made possible the conduct of over 30 autopsies^ 
and a number of brains have been forwarded to the Institute for special 
examination. Degeneration of the ganglion cells has been demonstrated 
and a thorough report of the pathology of kuru has been published. 

In searching for the cause of kuru, accurate mapping of the geo- 
graphical characteristics of the region, and a charting on these maps of 
the distribution of this disease was conducted. Its distribution 
corresponds closely to an isolated ethnic group called the "Fore" tribe. 
It lends a strong support to a genetic origin. 

A number of laboratory studies have been completed. Examination 
of blood serological specimens from patients and non-patients both in 
affected and non-affected areas has demonstrated the existence of an 
abnormality of the protein fraction, but the relationship of this to 
kuru has not been defined. 

Abnormalities of adrenal hormone compounds also have been demon- 
strated, and these have been associated with abnormalities of sodium and 
potassium levels in the blood serim, strongly suggesting the existence of 
some endocrine imbalance in this disease. The existence of some hormone 
imbalance is further suggested by a strong preponderance of the disease 
in small children and in women. 

In a further effort to establish a genetic relationship, blood 
grouping in this population is also being conducted, and over 2,000 



- 32 - 

specimens of blood serum have been obtained for this purpose. In 
addition to the blood grouping conducted with this serum, it also is 
being subjected to antibody studies in order to obtain information on 
the virus exposure and experience of this previously untouched population. 

GRADUATE TRAINING GRANTS 

The basis of our future research program will be a corps of 
qualified, v;ell-trained investigators. The major emphasis has therefore 
been upon grants to encourage and facilitate training of personnel for 
research in neurology. 

The training of clinical neurologists was the first program 
launched, and in 1958 comprised 55 units. It will train 80 to 90 
individuals each year as specialists in clinical neurology. The training 
of child specialists in this field is in an early stage, with 3 active 
programs in pediatric neurology at present training only 10 individuals. 
The critical lack of pediatric neurologists must be expected to continue 
unless this program can be greatly strengthened. 

Advance in the neurological sciences depends also on the training 
of basic science investigators, including neuropathology, neuroanatomy, 
neurophysiology, neuropharmacology, and neurochemistry. The emphasis of 
the training programs developed within these areas of basic science has 
been to provide a sound knowledge of this basic discipline, and in 
addition, a relationship to and an awareness of the clinical problems 
toward which these basic investigations are directed. A number of basic 



- 33 - 
science training programs were established in the latter half of the 
calendar year 1958' The number of trainees is still small, but repre- 
sents a 350 per cent expansion during this year. 

In the sensory disorders, the training grants in opthalmology 
were increased in I958 from 35 to 38; in otolaryngology from 6 to 18. 
In addition, a new area "sensory physiology" was instituted in 1958, 
whose purpose is to train men with Ph.D. or M.D, degree for research in 
the sensory disorders, A goal of 10 programs in this area by the end of 
1959 lias been set. 
Special traineeships 

The special traineeship program has as its objective, specialized, 
advanced training for individuals undertaking advanced research careers. 
The 1958 program increased approximately 50 percent over 1957^ and 
reached an expenditure of a support level of nearly $1 million. Under 
this program we have been able to support 125 trainees working in 50 
institutions in the United States, Canada, Europe, and South America. 
Although the majority of these traineeships are for individuals with an 
M.D. degree, this year 10 awards went to basic scientists holding the ■ 
Ph.D. degree. Almost without exception, men who have completed such 
traineeships move rapidly into academic positions and develop labora- 
tories undertaking independent research. 
Research fellowships 

The research fellowship program continued during 1958 at a 
steady level, half of the funds going to scientists working toward 



. 3h - 
Ph.D. degrees, or electing research after receiving Ph.D. or M.D. 
degrees. The remaining funds were used to support undergraduate students 
for part-time training and experience during the medical course. Experi- 
ence has indicated that the earlier in his career a medical student can 
be exposed to an opportunity for research, the more likely that this will 
prove his eventual career. 

INTERNATIONAL ASPECTS OF NEUROLOGY 

Neurology as a branch of medicine developed in Europe during the 
19th century and has long been given a significant place in the world 
medical picture. The Institute staff has participated in many inter- 
national developments including the 1955 planning committee for the 
Sixth International Neurological Congress in Brussels, Various papers 
were presented by Institute scientists at the Congress in 1957- 

Two significant events took place at the time of the International 
Congress. For the first time, representatives of many neurological 
disciplines met together for the First International Congress of 
Neurological Sciences. This included not only neurologists but also 
electroencephalographers, clinical neurophysiologists, neuropathologists, 
neurosurgeons, and other related scientists around the world. 

Also, at the time of the Congress, representatives of the neuro- 
logical societies of some twenty countries met together and founded the 
World Federation of Neurology. Its principal purpose is to serve as a 
formal representative body for the advancement of neurology and 



- 35 - 
neurological sciences throughout the world. This will be accomplished 
by the dissemination and exchange of new scientific knowledge, the 
stimulation of basic and clinical research, the organization of inter- 
national neurological congresses and symposia, and the encouragement of 
promising young men to pursue careers in neurology. 

With headquarters in Brussels, the World Federation now has more 
than 30 members including Canada, the United States, many South 
American countries, countries of the Middle East, Europe, India, 
New Zealand, Japan, and even Iron Curtain countries. This organization 
is well qualified to serve as the coordinating mechanism for various 
international programs. 

There is reason to believe that some of the answers to unsolved 
neurological problems could be found if we would pool all our detailed 
scientific information, review it carefully, and move forward on the 
basis of this new knowledge. In some instances this would undoubtedly 
lead to studies in the geographic and climatic distribution of disease. 
Studies of this nature have provided answers in the past. At the 
present time we are aware of a number of leads in this field such as the 
larger incidence of multiple sclerosis in cold climates. 

If climate is a major factor in multiple sclerosis and other 
diseases, perhaps an intensive study in a very v/arm as well as a cold 
climate on another continent would provide some leads. Perhaps the 
mineral content of water and food should be more closely observed in 



- 36 - 
other areas. These and many other types of studies referring to the 
evaluation of the frequency of disease and the relationship to genetic 
and environmental factors in diverse geographic regions and populations 
hold promise for the answers we are seeking. 

CONCLUSION 

The Institute is continuing its broad attack against disorders of 
the brain and nervous system. Emphasis is on the two extremes of age-- 
the tragic disabilities of the young which bear with them the specter 
of lifelong dependency, and the crippling conditions of old age which 
shorten the satisfying period of useful existence. The central core 
of this program has been financial support for individual investigators 
whose imagination and initiative represent the foundation of research. 

The recruitment of future scientists and their efficient training 
in superior skills constitute our capital investment in the future. The 
Institute's program for the training of investigators has increased in 
number of trainees from 11 in 1952 to 125 in 1958. The first awards 
were made almost exclusively for training for research in clinical 
neurology. This was next extended to include ophthalmology, 
otolaryngology, neurosurgery, and a combination of pediatrics with 
these specialties. The program is now being broadened to include the 
basic sciences of neuroanatomy, neurochemistry, neuropathology, 
neuropharmacology, neurophysiology, neuroradiology and virology of 
the nervous system. 



- 37 - 

The Institute's most recent research projects are in the area 
of cooperative and collaborative research. These programs bring 
together many investigators with a common area of interest at medical 
research centers across the Nation, and represent a technique for the 
mobilization of previously untapped resources. 

In summary, the Institute's program is encouraging an increasing 
number of veil-trained investigators to enter the field of neurological 
and sensory research, providing these individuals with the tools 
necessary for research progress, and strengthening the mechanism 
through which their work can be facilitated most effectively. 



OPENING STATEMENT 

Deputy Director, National Institutes of Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"Grants for Construction of Health Research Facilities" 



Mr. Chairman and Members of the Committee: 

The Health Research Facilities Act of I956 (Title VII of the 
Public Health Service Act, enacted as PL 835^ 84th Congress, amended 
by PL 777^ 85th Congress) authorized Public Health Service grants for 
construction of health research facilities. This Act was intended to 
provide health research facilities construction grants "to nonfederal 
public and nonprofit institutions for the constructing and equipping 
of facilities for research in the sciences related to health -- 
medicine, osteopathy, dentistry, public health, and fundamental and 
applied sciences when related thereto." 

The initial basic legislation authorized appropriations of 
$30,000,000 for each of three years -- 1957^ 1958, and 1959- Appropri- 
ations of the $30,000,000 were made by the Congress for 1957, 1958, 
and 1959- During the last Congress, this Act was extended to provide 
authorization of $30,000,000 for each of three additional years — 
i960, 1961, and 1962. The $20,000,000 requested for I96O, less than 
the authorized program level, is consistent with the Administration's 
policy of deferring construction starts. 



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The Surgeon General may award these construction grants only 
if the National Advisory Council on Health Research Facilities has 
recommended approval and the grantee institution has agreed to match 
the funds provided "by the Public Health Service in at least an equal 
amount. The Health Research Facilities Act of 1956 established this 
Council with the Surgeon General of the Public Health Service as Chainnan^ 
one ex officio member from the National Science Foundation^ and 12 
appointive members. 

Following the recommendations of the National Advisory Council 
on Health Research Facilities, the Surgeon General submitted the First 
Annual Report on January 15, 1957^ to the President, who submitted it 
to the Congress on February 6, 1957 • This report is identified as 
House Document No. 21, 85th Congress. The Second Annual Report was 
submitted by the President on February k, 1958^ and after referral to 
the House Committee on Interstate and Foreign Commerce was printed as 
House Document No. 32^. The Third Annual Report was submitted by 
the President to Congress on February 3^ 1959^ and was printed as 
House Document No. 73« 

PROGRESS REPORT ON GRAM'S AWARDED 

Since the beginning of the program 69O new, revised, and 
supplemental applications have been received in a total request of 
$193^817^^18. To date the Surgeon General has awarded k'^6 grants. 



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including supplement als, to 248 institutions in 45 states, the District 
of Columbia, and Hawaii. These grants total $90^000^000; ^^t represent 
a total construction volume of $500,278,183. 

Sixty-four medical schools have received I69 grants valued at 
$49A08,879i 12 dental schools have received Ik grants totaling 
$1,044,8C0; 3 schools of public health have received 5 grants in the 
total amount of $994,1^5; other school programs such as veterinary 
medicine, phannacy, chemistry, and biological sciences have received 
l46 grants in the total amount of $19,410,058; and other public and 
private nonprofit institutions other than schools have received I62 
grants valued at $19,442,118. 

Construction Progress -- This past year has shown considerable 
progress in the construction, completion, and utilization of new and 
renovated research facilities under this Program. As of December 31^ 1958, 
there were 98 completed projects representing a total construction cost 
of $64,164,682. These projects received a total of $12,011,906 in 
construction and equipment grants. An additional 68 projects were 
under contract at a total construction cost of $153>365,688. This 
latter group received $24,882,270 in facilities grants. 



- h 



Current Status -- As of March 10^ 1959^ ^95 grants to 248 
institutions in 45 States^ the District of Columbia and Hawaii have 
been avrarded for a total of .'.o 90; 000 ^000. Together v/ith these currently 
active projects; as of March 10^ 1959 there was an additional demand 
for program funds as follows : 

1. Approved projects recommended by the Council 

for payment from FY I96O funds when available $23,924,088 

2. Pending for review at the October 1959 Council meeting: 

(a) Applications deferred in February 1959 

for further study 2, 299^01^1- 

(b) New applications (including revisions and 
supplement als) received since February 1959 16, 066,462 

Total demand represented by formal applica- f)42,209;5o4 

tions 

3. Intentions to submit applications at future dates, 
many of which will be submitted formally prior to 

June 1, 1959 for review in October 1959 34,428,585 

Total additional program demand 'p7^;.Tl8,l49 



OPENING STATEl'/ffiNT 

by 
Associate Director, National Institutes of Health 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 
i960 ESTIMTE 
for 
"Research Facilities Construction and Site Acquisition' 



Mr. Chairman and Members of the Committee: 

The steadily increasing requirements for large animals by 
scientific personnel are an expression of the changing needs in medical 
research at the National Institutes of Health. The trend to long-term 
experiments (one to five years) with monkeys and dogs and the use of 
horses and sheep to provide serum and red blood cells for tissue culture 
and preparation of bacterial media are most pronounced. In 1950, the 
National Institutes of Health had only 25^ large animals (cats, dogs, or 
larger) for research purposes; at the present time there are about 
1,500 animals available at Bethesda and on the Rockville farm. In 1950 
there were 6 horses used for serum, red cells and tissue culture; there 
are now 1^+, and the number can reasonably be expected to double within 
the next five years. 

The long-term research studies continually build up a back-log 
of animals that must be housed for long periods, while at the same time 
space must be available for the processing and housing of additional 
animals needed by the research areas. Under these conditions, the large 
animal population steadily increases, yet many of the larger animals 
cannot be housed on the grounds at Bethesda. 



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Present housing facilities available on a temporary loan basis 
outside Rockville, Maryland, are limited to about six acres and are 
quite inadequate to meet present needs. There is no possibility of 
continued use of this space in the years ahead because land in the 
neighborhood is shifting to residential development. The present lease 
es^ires in two more years. Under the circumstances, the National 
Institutes of Health needs to acquire its own farm land in an area which 
will not make untenable its purposes as a large animal holding facility. 

A site to meet anticipated National Institutes of Health require- 
ments should be generally of a rectangular shape consisting of about 
UOO to 500 acres and within a reasonable driving distance of Bethesda 
on hard surfaced roads. The terrain should be such that facilities 
may be situated in the center of the property to obviate the nuisance 
factors inherent in housing a number of large animals. Investigations 
into the possibility of acquiring presently owned government land in 
nearby areas revealed that there are no available sites suitable to our 
requirements. However, a choice of sites is available in nearby farm 
communities. Land values vary considerably in this area ranging from 
$250 to as much as $1,500 per acre, and have shown sharp increases in 
the past few years. Sites suitable for the National Institutes of Health 
needs are currently selling for approximately $400 per acre. Since the 
need for such a facility is pressing, and since land values are steadily 
rising in the area, it is requested that funds be made available to 
acquire the necessary property as early as possible. 



OPENING STATEMINT 

Associate Director, National Institutes of Health, 
Public Health Service 

COMMITTEE ON APPROPRIATIONS 

i960 ESTIMATE 

for 

"Construction of Animal Quarters, Hamilton, Montana" 



Mr. Chairman and Members of the Committee: 

The Rocky Mountain Laboratory at Hamilton, Montana, because of its 
geographical location, is almost entirely dependent upon its own resources 
for breeding and rearing the experimental animals needed in the conduct 
of its research programs. In 19^9 a temporary wood frame stmcture was 
built at Hamilton to accommodate animal production, primarily for the 
rearing of mice. The situation has now developed to the point that the 
research of the laboratory is hampered through lack of an adequate supply 
of experimental animals. 

This increased need has developed as a result of the gradual growth 
of the laboratory and recently through the initiation of several new re- 
search studies which are dependent upon larger animals for experimental 
p\irposes. One of the new programs recently started involves work directed 
toward development and improvement of vaccines. One study concerns basic 
work to improve a tuberculosis vaccine. There is evidence that it may be 
possible to produce such a vaccine by using specific parts of the tubercle 
bacilli; however, the progress of this research depends upon the use of 
rabbits for testing purposes. In addition to research on vaccine 



- 2 - 
development, the Rocky Mountain Laboratory has gradually expanded its 
activities to include research relating to allergy. Studies in this 
area are likewise dependent upon rabbits and guinea pigs. As a result 
there has been pressure on the production facilities of the laboratory to 
obtain an adequate supply of these animals for studies now under way to 
the extent that the needs of the research programs of the Rocky Mountain 
Laboratory for experimental animals can no longer be met. 

The soundest way to resolve the problem is to construct a building 
for rearing the rabbits and guinea pigs essential to the research needs 
of the laboratory. The proposed building would be approximately l60' by 
50', cement slab, single story, structiiral tile walls and composition 
roof. Cage washing facilities are included. Cost of the basic con- 
struction, including the essential mechanical and service installations 
needed in the operation of the building, is estimated at $150,000. The 
utilities, including heat for the building, will be supplied by connection 
to the existing steam and power sources of the laboratory. The building 
would be constructed on land which belongs to the United States Government 
and is a part of the present 19-acre plot on which the Rocky Mountain 
Laboratory is located. Much thought and planning has already gone into 
this problem. Because the need is so pressing and in order to save time, 
engineering drawings and specifications have been prepared and are 
essentially ready for final approval and release for bid. It is estimated 
that from the date funds are made available seven months would be required 
to complete construction. 



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